No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
A review of propolis antitumor action in vivo and in vitro
Abstract
Epidemiologic findings strongly suggest that cancer rates are influenced by environmental factors that can be mitigated to a great extent, for example by a diet rich in polyphenolic/flavonoid compounds. Among natural products, honeybee propolis has been applied for centuries in traditional medicine as well as in diets and supplementary nutrition. Honeybee propolis and its polyphenolic/flavonoid compounds have been known to exhibit biological activity including immunopotentiation, chemopreventive and antitumor effects. In this review we consider the inhibition of tumor growth by honeybee propolis and their polyphenolic/flavonoid compounds as well as the mechanisms involved based on in vivo and in vitro studies. Results have shown that propolis and its polyphenolic compounds exerted an anti-metastatic and antitumor effect in mice and rats and considerable cytotoxicity without cross-resistance in both wild-type and chemoresistant human tumor cell lines. These findings suggest that propolis and their polyphenolic/flavonoid components may serve as a potent adjunct to chemotherapy and radiotherapy in the treatment of cancers. However, further in-depth studies including clinical trials are needed to fully evaluate the value of flavonoids in combination with chemotherapeutic agents for the treatment of human cancers.
... Prostate cancer (7.3%) and non-melanoma of skin (6.2%) and colon cancer (6%) are the rest of the top five most commonly diagnosed cancers. Lung cancer is the most common cause of death Regardless of its plant source and chemical profile, propolis consistently exerts antimicrobial, antioxidative, immunomodulatory, anti-inflammatory, anti-allergic, dermaprotective, laxative, anti-diabetic, anti-angiogenic, and antitumor activity [8][9][10][11][12][13]. The antimicrobial activity is attributed to flavonoids such as pinocembrin, galangin, pinobanksin, pinobanksin-3-acetate, and caffeic acid esters. ...
... Therapeutic effects of propolis on numerous diseases, such as infections, hypertension, cardiovascular disorders, diabetes, allergies, asthma, and cancer, are assigned to its antioxidative, immuno-modulatory, and anti-inflammatory properties [3,[8][9][10][11][12][13][14][15][16][17][34][35][36][37][38][39][40][41][42][43]88]. These diseases are accompanied by mitochondrial dysfunction and increased ROS production and the enzymatic and non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs). ...
... Several mechanisms have been implicated in the inhibition of cell proliferation: (i) inhibition of the activity of tyrosine-specific protein kinases [126][127][128], such as inhibition of PKC, which is one of the key enzymes in the regulation of cellular proliferation and tumor growth; (ii) induction of the differentiation of carcinoma cells [3,13,[126][127][128][129]; (iii) transcriptional changes in cell cycle-and apoptosis-related genes such as NF-κB, Bcl-X(L) and COX-2; (iv) binding to the estrogen receptor and inhibition of an estrogen receptor-positive human breast cancer cells [130,131]; (v) induction of apoptosis, (vi) downregulation of the expression of mutated H-Ras and p53 tumor suppression gene [3,13,126], (vii) modulation of gene methylation and re-expression of tumor suppressors or other genes silenced by aberrant DNA methylation [119,130,131], (viii) inhibition of pro-oxidative enzymes xanthine oxidase, cyclooxygenases, or lipooxygenases [3,13,126,127], and (ix) some flavonoids are a direct poison for topoisomerase II (TopoII), through the stabilization of double strand breaks in the TopoII-DNA cleavage [4,[9][10][11][12][13]. ...
In recent years, interest in natural products such as alternative sources of pharmaceuticals for numerous chronic diseases, including tumors, has been renewed. Propolis, a natural product collected by honeybees, and polyphenolic/flavonoid propolis-related components modulate all steps of the cancer progression process. Anticancer activity of propolis and its compounds relies on various mechanisms: cell-cycle arrest and attenuation of cancer cells proliferation, reduction in the number of cancer stem cells, induction of apoptosis, modulation of oncogene signaling pathways, inhibition of matrix metalloproteinases, prevention of metastasis, anti-angiogenesis, anti-inflammatory effects accompanied by the modulation of the tumor microenvironment (by modifying macrophage activation and polarization), epigenetic regulation, antiviral and bactericidal activities, modulation of gut microbiota, and attenuation of chemotherapy-induced deleterious side effects. Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents, likely by blocking the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In this review, we summarize the current knowledge related to the the effects of flavonoids and other polyphenolic compounds from propolis on tumor growth and metastasizing ability, and discuss possible molecular and cellular mechanisms involved in the modulation of inflammatory pathways and cellular processes that affect survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.
... [5][6][7][8] The anticancer mechanism and antioxidant, antiinflammatory and antiproliferative activities of quercetin are mainly associated with the inhibition of bioactive enzymes and detoxification enzymes. [9] Therefore, quercetin is a promising anticancer drug [9,10] whose activity has been confirmed in several cancers including breast, [11] colon, [12] gastric, [13] leuke- mic, [14] ovarian [15] and bladder cells. [4,16] Anticancer actions have been attributed to several cellular mechanisms including apoptosis by triggering the generation of reactive oxygen species (ROS), stress proteins, disruption of microtubules and mitochondria, caspase activation and reduction in expression of survivin protein [9][10][11][12][13][14][15] and regulation of the cell cycle by modulating several molecular targets including p21, [9,17] cyclin B, [11] p27 [18] and topoisomerase II. ...
... [5][6][7][8] The anticancer mechanism and antioxidant, antiinflammatory and antiproliferative activities of quercetin are mainly associated with the inhibition of bioactive enzymes and detoxification enzymes. [9] Therefore, quercetin is a promising anticancer drug [9,10] whose activity has been confirmed in several cancers including breast, [11] colon, [12] gastric, [13] leuke- mic, [14] ovarian [15] and bladder cells. [4,16] Anticancer actions have been attributed to several cellular mechanisms including apoptosis by triggering the generation of reactive oxygen species (ROS), stress proteins, disruption of microtubules and mitochondria, caspase activation and reduction in expression of survivin protein [9][10][11][12][13][14][15] and regulation of the cell cycle by modulating several molecular targets including p21, [9,17] cyclin B, [11] p27 [18] and topoisomerase II. ...
... [9] Therefore, quercetin is a promising anticancer drug [9,10] whose activity has been confirmed in several cancers including breast, [11] colon, [12] gastric, [13] leuke- mic, [14] ovarian [15] and bladder cells. [4,16] Anticancer actions have been attributed to several cellular mechanisms including apoptosis by triggering the generation of reactive oxygen species (ROS), stress proteins, disruption of microtubules and mitochondria, caspase activation and reduction in expression of survivin protein [9][10][11][12][13][14][15] and regulation of the cell cycle by modulating several molecular targets including p21, [9,17] cyclin B, [11] p27 [18] and topoisomerase II. [9,17] The aim of this study was to investigate the possible direct cytotoxic and genotoxic effects of quercetin on human bladder cancer T24 cells by MTT test, colony forming assay and alkaline comet assay after short time exposure (2 h) that would be applied directly to urinary bladder cancer patients. ...
In an effort to improve local bladder cancer control, we investigated the cytotoxic and genotoxic effects of quercetin on human bladder cancer T24 cells. The cytotoxic effect of quercetin against T24 cells was examined by MTT test, clonogenic assay as well as DNA damaging effect by comet assay. In addition, the cytotoxic effect of quercetin on the primary culture of papillary urothelial carcinoma (PUC), histopathological stage T1 of low- or high-grade tumours, was investigated. Our analysis demonstrated a high correlation between reduced number of colony and cell viability and an increase in DNA damage of T24 cells incubated with quercetin at doses of 1 and 50 µM during short term incubation (2 h). At all exposure times (24, 48 and 72 h), the efficacy of quercetin, administered at a 10× higher dose compared to T24 cells, was statistically significant (P < 0.05) for the primary culture of PUC. In conclusion, our study suggests that quercetin could inhibit cell proliferation and colony formation of human bladder cancer cells by inducing DNA damage and that quercetin may be an effective chemopreventive and chemotherapeutic agent for papillary urothelial bladder cancer after transurethral resection.
... 13,16,19 It was demonstrated that propolis has pronounced immunomodulatory effect, [20][21][22][23][24][25][26] antioxidant effect, 17,[27][28][29] and antitumor effect both in vitro and in vivo. [20][21][22][23][24]29,30 Chemopreventive and direct antitumor effect of propolis is based on preventing carcinogen metabolic activation, preventing tumor cell proliferation by inactivation or downregulation of prooxidant enzymes or signal transduction enzymes, and induction of apoptosis. 13,16,24,30 Indirect antitumor effect of propolis is based on its antioxidative properties via scavenging of free radicals and increasing the activities of antioxidant enzymes, and immunomodulating properties via macrophage activation. ...
... [20][21][22][23][24]29,30 Chemopreventive and direct antitumor effect of propolis is based on preventing carcinogen metabolic activation, preventing tumor cell proliferation by inactivation or downregulation of prooxidant enzymes or signal transduction enzymes, and induction of apoptosis. 13,16,24,30 Indirect antitumor effect of propolis is based on its antioxidative properties via scavenging of free radicals and increasing the activities of antioxidant enzymes, and immunomodulating properties via macrophage activation. 16,20,21,[25][26][27] Much information can be gained by investigating the consequences of hyperthermia on individual cell populations in vitro; however, the precise effects of such a therapeutic modality in vivo depend on the tumor microenvironment and the cellular composition therein. ...
... It is well established, for example, that chemopreventive effect of WSDP could result from increased activity of antioxidant enzymes and scavenging of free radicals, the production of which is enhanced during chemotherapy with cisplatin. The scavenging of chemotherapyinduced free radicals could also be one of the important mechanisms of chemoprevention by WSDP, which was confirmed by Chen et al. 30 and Refs. 16,29,60,61, showing that propolis and related polyphenolic compounds exercise their activity through the scavenging of hydroxyl, superoxide free radicals, and lipid peroxides. ...
... Propolis has a wide spectrum of biological and pharmacological properties, which have been intensively researched in cell and animal experiments and thus it can be considered as a drug from the beehive [3]. Recently, studies concerning propolis and cancer have been attracting researchers [9][10][11]. Propolis and its components, namely, caffeic acid, caffeic acid phenethyl ester (CAPE), 3,5-diprenyl-4-hydroxycinnamic acid (artepillin C), and others, are frequently mentioned in the literature as antitumor and immunomodulatory agents [9,10,12]. ...
... Recently, studies concerning propolis and cancer have been attracting researchers [9][10][11]. Propolis and its components, namely, caffeic acid, caffeic acid phenethyl ester (CAPE), 3,5-diprenyl-4-hydroxycinnamic acid (artepillin C), and others, are frequently mentioned in the literature as antitumor and immunomodulatory agents [9,10,12]. Through in vitro and in vivo assays it was possible to define different mechanisms of actions for the bee glue and its components, such as suppressing cancer cells proliferation via its anti-inflammatory effects, decreasing the cancer stem cell populations, blocking specific oncogene signaling pathways, exerting antiangiogenic effects, and modulating the tumor microenvironment [9][10][11]. ...
... Propolis and its components, namely, caffeic acid, caffeic acid phenethyl ester (CAPE), 3,5-diprenyl-4-hydroxycinnamic acid (artepillin C), and others, are frequently mentioned in the literature as antitumor and immunomodulatory agents [9,10,12]. Through in vitro and in vivo assays it was possible to define different mechanisms of actions for the bee glue and its components, such as suppressing cancer cells proliferation via its anti-inflammatory effects, decreasing the cancer stem cell populations, blocking specific oncogene signaling pathways, exerting antiangiogenic effects, and modulating the tumor microenvironment [9][10][11]. ...
With a complex chemical composition rich in phenolic compounds, propolis (resinous substance collected by Apis mellifera from various tree buds) exhibits a broad spectrum of biological activities. Recently, in vitro and in vivo data suggest that propolis has anticancer properties, but is the cytoxicity of propolis specific for tumor cells? To answer this question, the cytotoxicity of phenolic extracts from Portuguese propolis of different origins was evaluated using human tumor cell lines (MCF7-breast adenocarcinoma, NCI-H460-non-small cell lung carcinoma, HCT15-colon carcinoma, HeLa-cervical carcinoma, and HepG2-hepatocellular carcinoma), and non-tumor primary cells (PLP2). The studied propolis presented high cytotoxic potential for human tumor cell lines, mostly for HCT15. Nevertheless, excluding HCT15 cell line, the extracts at the GI50 obtained for tumor cell lines showed, in general, cytotoxicity for normal cells (PLP2). Propolis phenolic extracts comprise phytochemicals that should be further studied for their bioactive properties against human colon carcinoma. In the other cases, the proximity of the in vitro cytotoxic doses for tumor and normal cell lines should be confirmed by in vivo tests and may highlight the need for selection of specific compounds within the propolis extract.
... In addition, administration of AEP to the mouse significantly inhibited the growth of transplanted tumor cells (Inoue et al., 2008). Orsolic (2010) states that the chemopreventive activity of propolis in animal models and cell cultures is due to its ability to inhibit DNA synthesis in tumor cells, to induce tumor cells to apoptosis, and to activate macrophages that produce factors that regulate the functions of B-, T-and NK-cells. ...
... Numerous studies have been demonstrated the effect of propolis on cell culture and animal testing (Awale et al., 2008;Orsolic, 2010;Catchpole et al., 2015). In other words, several studies indicating that propolis can be consumed with regular anticancer effect. ...
Propolis is a special resin and wax material collected from the leaves and shells of trees, buds and shoots of plants by honey bees (Apis mellifera L.). In recent years, many researchers have studied the chemical composition, biological activity and pharmacological properties of propolis. The colour, odour and pharmacological properties of the propolis composition also vary as the composition changes depending on the plant, region, season and bee colony. Flavonoids, aromatic acids, phenolic acids and esters are the main compounds responsible for the biological activity of propolis. A number of studies have been conducted on the use of propolis or its active ingredients in the treatment of cancer. It has been observed that the use of propolis did not cause side effects according to in-vitro and in-vivo studies. Propolis should be extracted with different compounds for use in biological assays. The most commonly used compounds for extraction are ethanol, methanol, oil and water. A number of studies have been carried out showing the antitumor effect of propolis in cell culture and animal tests. The search for new drugs derived from natural products, which may function as chemotherapeutic agents and have low side effects, has increased in recent years. Combination with antioxidant therapy may improve the side effects of chemotherapy on leukocytes, liver and kidney, thus increasing the effect of chemotherapy with dose increase.
... Propolis, an apitherapeutic product, is a natural product that should be highlighted in terms of its content of highly effective compounds. One of the most studied compounds of propolis is CAPE (20,21). It is known that there is a synergistic effect between propolis and anticancer agents, and that blast cells are directed to apoptosis and cell differentiation due to this effect (22,23). ...
... Numerous studies have been reported showing the antioxidant (Nagai et al. 2003, Ozdal et al. 2019, anti-inflammatory (Araujo et al. 2012), antibacterial (Uzel et al. 2005, Przybyłek and Karpiński 2019, Almuhayawi 2020), antiviral (Schnitzler et al. 2010, Kwon et al. 2020, antifungal (Özcan 1999, 2 Elgin et al. Temiz et al. 2013), and antitumour (Oršolić 2010, Sawicka et al. 2012, Patel 2016) activities of various propolis samples. Due to these activities, the pharmacological potential of propolis has been the subject of many studies (De Castro 2001, Sforcin and Bankova 2011, Silva-Carvalho et al. 2015. ...
Aims:
Propolis is a resinous bee product containing several hundred biologically active compounds. Although the antibacterial activity of propolis has been demonstrated in many in vitro studies, less is known about its mode of action. In this study, we aimed to shed some light on the antibacterial mechanism of action of propolis against Escherichia coli BW25113 using a nuclear magnetic resonance (NMR) based metabolomics approach.
Methods:
E. coli BW25113 cells were subjected to different sub-lethal concentrations (0, 2, 4, and 6 mg/mL) of Turkish propolis water extract (PWE). The 500-MHz 1H NMR spectroscopy was then employed to ascertain the metabolic profiles of E. coli extracts.
Results:
A total of 52 metabolites were identified from the NMR spectra, belonging to 17 main classes, such as amino acids and peptides, purines, and fatty acids. Twelve out of these 52 metabolites displayed remarkable changes at all tested PWE concentrations when compared to control conditions (P < .05). Levels of 28 more metabolites were significantly altered in at least one of the three PWE treatments. The results of partial least squares discriminant analysis showed that there was a clear separation between control and propolis-treated cells and that putrescine, adenine, adenosine, guanosine, glucose, N6-acetyllysine, and acetamide had the highest effect on group differentiation. Finally, quantitative pathway analysis revealed that purine metabolism was significantly affected by PWE treatments.
Conclusions:
Our results suggest that PWE inhibits the growth of E. coli BW25113 by affecting nucleic acid metabolism to a great extent. To the best of our knowledge, this is the first study to evaluate the global metabolic response of a bacterium to propolis.
... At folk medicine, the Greek physicians used the raw propolis for improving of the gastrointestinal functions, anti-aging, inhibit tumor, anti-fatigue as well as others benefits. The propolis has powerful anti-inflammatory and antioxidant properties which that defense the damaging affects against aluminum toxicity (8)(9)(10) . This study aimed to evaluate the toxicity of aluminum silicate (AIS) admitted to rat models among their organs (liver, lung and cerebellum tissues). ...
... Propolis has continued its popularity in protecting human health and preventing diseases until recent years (Cao et al., 2017). Its ability to inhibit DNA synthesis in tumor cells and capacity to induce apoptosis has been revealed (Oršolić, 2010). Moreover, the anti-inflammatory activity of propolis has been proposed in guinea pig mast cell investigations (Almeida & Menezes, 2002). ...
Propolis is the extract of a resinous compound that protects plants from both cold and microorganism attack and has gained a strong and sticky property because it is transformed after being collected by honey bees. Up to date, many studies have shown that propolis exhibited various beneficial biological activities, such as antifungal, antibacterial, antiviral, antioxidant, antimutagenic, and antitumor effects. Recent reports propounded the in vitro and in vivo neuroprotective effect of propolis; however, the exact molecular genetic mechanisms are still unclear. Therefore, we aimed to investigate the toxicogenomic and beneficial properties, including cytotoxic, antioxidant, apoptotic/necrotic as well as genotoxic effects of propolis (1.56–200 µg/ml) on differentiated SH‐SY5Y neuronal cells. Additionally, microarray analysis was conducted on cell cultures following propolis application to explore gene differentiation. Differentially expressed genes were further analyzed using string software to characterize protein–protein interactions between gene pathways. Our results revealed that propolis applications could not have a prominent effect on cell viability even at concentrations up to 200 µg/ml. The highest propolis concentration induced apoptotic rather than necrotic cell death. The alterations in gene expression profiles, including CYP26A1, DHRS2, DHRS3, DYNC1I1, IGF2, ITGA4, SVIL, TGFβ1, and TGM2 could participate in the neuroprotective effects of propolis. In conclusion, propolis supplementation exerted remarkable advantageous; thus, it may offer great potential as a natural component in the prevention and treatment of neurodegenerative disorders. Whole‐genome gene expression pattern following propolis application was investigated for the first time in neuronal cell culture to fill a gap in the literature about propolis toxicogenomics.
Practical applications
Propolis is a very rich product in terms of benefits. In addition to its antibacterial, antiviral, antifungal, and anti‐inflammatory content, it is known to have preventive and therapeutic properties for many different ailments. On the other hand, molecular mechanisms of propolis on gene expression differentiations haven't been investigated until now. Moreover, gene expression pattern is vital for all living organisms to maintain homeostasis. Thus, we conduct an experiment series for analyzing gene expression differentiation effects on neuronal cells to understand beneficial properties of propolis. Hence, it could be possible to comment on the use of propolis as a nutritional factor and beneficial diet.
... Despite our findings in this study, the therapeutic activities of bee products related primarily to the presence of flavonoids that modulate steroid hormones (phytoestrogen activity) and consequently hormonedependent ovarian activity have been suggested [29,30], as well as their capacity to interact with estrogen receptors-β in the reproductive organs [31]. In vitro studies showed that bee pollen regulates the insulin-like growth factor-1 released by mammalian ovarian granulosa cells, which is important for the regulation of ovarian functions [27]. ...
Bee pollen, a natural resource collected by bees, is rich in many nutrients, therefore it may represent a useful dietary supplement. Different uses of bee pollen are proposed due to its beneficial health properties, which includes the capacity to improve animal performance and promote immunostimulation. Animal nutrition can directly affect adults and their offspring, and larval stage is a critical moment for fish due to high mortality related to immune challenges. Thus, the present study attempted to evaluate the effects of adding bee pollen to a zebrafish diet, specifically, analyzing the effects on reproduction and immunity transference to descendants. Zebrafish adults received control diets based on commercial flakes and live food Artemia sp. nauplii or bee pollen-supplemented diets, administered three times a day, at the same time. The animals received the diets over 60 d, and throughout this period, they were tested for: egg production per female, total number of eggs, embryo viability rate, larval survival rate after exposure to spring viremia of carp virus and to Salmonella enterica serovar Typhimurium, and larval neutrophil recruitment after tail wounding. Bee pollen supplementation failed to improve egg production and embryo viability, and was unable to substitute flakes in zebrafish breeders. Instead, the offspring of breeders fed with bee pollen supplemented diets showed longer survival upon virus exposure and higher neutrophil migration to wounds. These results indicate that bee pollen can influence vertical immunity through important mechanisms related to offspring immunity in the early stages, when larval immune system is not fully developed.
... The protective effect of H and CUR observed in this study may be related to the reduction of oxidative stress and apoptotic damage in the kidneys of 5-FU-treated mice. Urea and creatinine are among the most prominent determinants of kidney damage (Nada 2010). As previously reported, 5-FU-induced kidney damage is evident with increased urea and serum creatinine levels. ...
Nephrotoxicity is a very important complication of 5-fluorouracil (5-FU)–treated cancer patients. Increased oxidative stress, kidney damage, and apoptosis play an important role in the pathogenesis of nephrotoxicity caused by 5-FU. In this study, protective effects of two natural compounds, hesperidin and curcumin, on experimentally induced kidney damage in mice with 5-FU were determined. Application of 5-FU resulted in severe histopathological changes and severe renal failure with increased serum urea and creatinine levels. Also, 5-FU–induced kidney damage, increased levels of malondialdehyde (MDA), decreased superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) activity, and glutathione (GSH) level have been demonstrated. Also, where 5-FU is in the concentration of caspase-3 and 8-OHdG immune-positive cells and therefore causes apoptosis and DNA damage in kidney tissue cells. However, especially high doses of hesperidin and curcumin treatment significantly improved 5-FU–induced oxidative stress/lipid peroxidation, apoptosis/DNA damage, and renal dysfunction. Based on these data, our results suggest that hesperidin and curcumin may be used as new and promising agents against 5-FU–induced nephrotoxicity.
... It has been reported that propolis exhibits potent anti-cancer/chemoprotective activity in many models (cell line/animal/human) of head and neck, lung, liver, brain, pancreas, kidney, prostate, skin, breast, oral, esophagus, gastric, colon, and bladder cancers through modulation of various signaling molecules. These include COX, lipoxygenase (LOX), inducible NOS, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), NF-kB, TSG (p53 and p21), mitogen-activated protein kinases (MAPKs), metalloproteinases (MMPs), caspases, Bax/ Bcl2, TNF-related apoptosis-inducing ligand (TRAIL), and nuclear factor erythroid 2-related factor 2/heme oxygenase [11,16,17,19]. ...
Propolis is a bee wax rich in various phytocomponents and traditionally used to treat various ailments. Propolis is reported to possess an array of biological properties including anti-inflammatory, antioxidant, anti-cancer, and anti-diabetic as well as cardioprotective, hepatoprotective, renoprotective, and derma protective activities. A plethora of studies confirmed that propolis is effective against various types of cancer including head and neck, lung, liver, brain (glioma), pancreas, kidney, prostate, skin (melanoma), breast, oral, esophagus, gastric, colorectal, and bladder cancers. However, many researchers have demonstrated that propolis displays potent chemoprotective/chemopreventive or anti-cancer activity against only a few types of cancers like oral, gastrointestinal, dermal (melanoma), breast, and prostate cancers. Therefore, this mini-review only summarizes the chemopreventive/chemotherapeutic activities of propolis and its updated underlying mechanisms. Taken together, propolis displays potent chemoprotective or anti-cancer effect due to the presence of various phytocomponents which contribute to pro-apoptotic, cytotoxic, anti-proliferative (cell cycle arrest), anti-metastatic, anti-invasive, anti-angiogenic and anti-genotoxic or anti-mutagenic properties along with antioxidant, immunomodulatory, and anti-inflammatory functions. Hence, propolis could be used as an adjuvant for treating various cancers along with standard chemotherapeutic drugs. However, many large-scale clinical studies are needed to justify such applications.
... PR is composed of a variety of compounds including resins and vegetable balsam, bee wax, essential and aromatic oils, pollen grains, small amounts of vitamins, and other components with more than 300 bioactive factors such as flavonoids, phenolic acids, diterpenoids, and triterpenoids [24,25]. With different biological characteristics such as antibacterial, anti-inflammatory, antitumor, and potent antioxidant [26][27][28][29], PR has also been used to prevent UL in recent studies [30,31]. The antitumor characteristic of PR has been proven to be related to its antiproliferative capacity [32]. ...
The aim of this study was to evaluate the effects of aluminum sulfate (alum) with propolis (PR) on uterine leiomyoma (UL) in rat model. One hundred and four female Wistar rats (180–200 g) were allocated into two main groups of control (Co, n = 8) and experiment (UL model [estradiol benzoate 200 μg/kg/IM twice/week/8 weeks] with/without treatment) defined in 13 subgroups with/without treatment with coil oil (UL + COi), PR (100 or 200 mg/kg) as UL + PR100 or 200, alum (35, 75 or 150 mg/Kg) as UL + AL 35, 75, or 150, and PR (100 mg/kg or 200) with alum (35, 75, or 150 mg/Kg) as UL + PR100 or 200 + AL35, 75, or 150. Subgroups received doses of therapeutics for 14 days (IP). In the end, rats were sacrificed, and the uteri were isolated for molecular and histopathological investigations. The myometrium thickness, collagen contents, and gene expression of MMP-2 and 9 increased significantly in experimental groups with/without treatment (P ˂ 0.05). PR administration (100 and 200 mg/kg) alone or with alum (35 and 75 mg/kg) significantly decreased myometrium collagen contents and the gene expression and protein concentration of MMP-2 and 9 compared with UL and UL + Coi subgroups (P ˂ 0.05). Alum (75 mg/kg) with PR (200 mg/kg) could improve UL features and reduce MMP-2 and 9 gene expression.
... It has a strong cytoprotective effect against various exogenous harmful and toxic agents (Rizk, Zaki, & Mina, 2014). The chemical compositions of propolis are beneficial to bees and also have an important pharmacological value as a natural mixture (Oršolić, 2010). Currently, propolis is used in medical and dental sciences based on its chemical composition and its therapeutic properties (Elmenoufy, 2012). ...
Background
The use of natural products is an essential way to new pharmaceutical leads for the discovery and development of new drugs to treat diseases. Propolis (Pro) is a natural resinous product produced by honey bees. It has a strong cytoprotective effect against various exogenous toxic agents. The current study was designed to evaluate the possible protective effect of propolis against the toxicity of aluminum chloride (AlCl 3 ) on hepatorenal structure and function in male white albino rats.
Methods
Thirty mature males of albino rat, Rattus rattus , weighing about 80-90g were divided into five groups contained 6 rats each. The first group acts as a control (received only saline solution); the second group (Al) had given orally 40 mg/kg b.w. of AlC1 3 , the third group (Pro) had administrated orally 150 mg/kg b.w. of propolis and the fourth group (Al+Pro) had given 40 mg/kg b.w. of AlCl 3 in the morning and 150 mg/kg b.w. of propolis in the evening. These four groups had given the treatments for two months. The fifth group (Al-Pro) had given 40 mg/kg b.w. of AlC1 3 chloride for one month then had given 40 mg/kg b.w. of AlCl 3 combined with 150 mg/kg b.w. of propolis for another month.
Results
The AlCl 3 -treated group showed a significant increase in the activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), acid phosphatase (AP), and lactate dehydrogenase (LDH) in the plasma. Also, glucose, total protein, albumin, creatinine, uric acid, urea, cholesterol, and triglycerides in the plasma were significantly increased. The histological examination for the liver and kidney sections revealed marked histopathological alternations. The treatment with propolis combined with AlCl 3 improved the previous mentioned biochemical and histological alterations induced by AlCl3.
Conclusion
It can be concluded that the combination of propolis with AlCl 3 alleviated the toxic effects of AlCl 3 . The propolis has protective influences on the hepatorenal structure and function and could be able to resist AlCl 3 intoxication.
... It is known that many bee products, such as royal jelly, honey, pollen, propolis and bee venom, display antitumor and chemo-preventive activity and can be evaluated as alternative strategies for cancer treatment [19][20][21][22]. Propolis, a natural resinous bee product, has been used since ancient times as a traditional remedy for the treatment of various diseases, and in recent years its anticancer potential has been demonstrated [23][24][25][26]. The therapeutic effects of propolis depend on its chemical composition, which is related to the geographical area of origin and the environmental conditions of its production [27][28][29]. ...
The majority of deaths related to colorectal cancer (CRC) are associated with the metastatic process. Alternative therapeutic strategies, such as traditional folk remedies, deserve attention for their potential ability to attenuate the invasiveness of CRC cells. The aim of this study is to investigate the biological activity of brown Cuban propolis (CP) and its main component nemorosone (NEM) and to describe the molecular mechanism(s) by which they inhibit proliferation and metastatic potential of 2 CRC cell lines, i.e., HT-29 and LoVo. Our results show that CP and NEM significantly decreased cell viability and inhibited clonogenic capacity of CRC cells in a dose and time-dependent manner, by arresting the cell cycle in the G0/G1 phase and inducing apoptosis. Furthermore, CP and NEM downregulated BCL2 gene expression and upregulated the expression of the proapoptotic genes TP53 and BAX, with a consequent activation of caspase 3/7. They also attenuated cell migration and invasion by inhibiting MMP9 activity, increasing E-cadherin and decreasing β-catenin and vimentin expression, proteins involved in the epithelial–mesenchymal transition (EMT). In conclusion NEM, besides displaying antiproliferative activity on CRC cells, is able to decrease their metastatic potential by modulating EMT-related molecules. These finding provide new insight about the mechanism(s) of the antitumoral properties of CP, due to NEM content.
... At folk medicine, the Greek physicians used the raw propolis for improving of the gastrointestinal functions, anti-aging, inhibit tumor, anti-fatigue as well as others benefits. The propolis has powerful anti-inflammatory and antioxidant properties which that defense the damaging affects against aluminum toxicity (8)(9)(10) . This study aimed to evaluate the toxicity of aluminum silicate (AIS) admitted to rat models among their organs (liver, lung and cerebellum tissues). ...
Background: the liver is a critical organ because it contains most of the accumulated metals where toxic effects can expected. Also, the lung is directly affected by receiving aluminum as aluminum silicate. Exposure of aluminum leads to production of free radicals that damage living organs and tissues. Aim of the work: this study aimed to evaluate the nucleic acid content in liver, lung and cerebellum tissues intoxicated by aluminum silicate (AlS) and the possible ameliorative effect of propolis extract (PP). Material and methods: Forty male albino rats (weighting 100-120 grams) were categorized randomly into four groups, ten rats on each group (n=10). The 1st group considered as the healthy control group. The 2nd group received 200 ml PP/kg b.wt., day after day by stomach gavage. The 3 rd group was injected intraperitoneally by 20 mg AlS/kg b.wt., twice weekly. The 4th group was treated with AlS in addition to PP as the same doses as in the 2nd and 3rd groups. After two months for each group. Liver, lung and cerebellum organs were harvested. Results: decreased body weight gain of rats was realized with weakly stained nucleic acids contents in liver, lung and cerebellum tissues that intoxicated by AlS. While, using the supplemented treatment (PP) at the same time with the induction of AlS compound showed an ameliorative effect on the nucleic acid contents. Conclusion: propolis has anti-oxidant by inhibiting AlS toxicity on nucleic acids in the different experimental organs of rats.
... According to Orsolic, the chemical properties of propolis are not only beneficial to honey bees but have general pharmacological value to humans as a natural mixture. Propolis health food is useful component which regulate the physiological functions of the body plays a beneficial health effects (ORŠOLIĆ, 2010). ...
Objective of the study was evaluation of the harmful effect induced by
aluminum silicate in bone marrow chromosomes and liver tissues. Also, how
could prevents this toxicity. 60 Adult male albino rats weighing 100-120 g
were used for our experiments. The animals were divided into six equal
groups: first normal healthy control group, second group was given 200 ml
propolis/Kg day after day by stomach gavage, third group received low dose
of aluminum silicate (5 mg/kg; intra peritoneal) twice a week, forth group
injected with high dose of aluminum silicate (20 mg/kg; intra peritoneal)
twice a week, fifth group received propolis and aluminum silicate with
similar doses as that of second & third groups and sixth group received
propolis and aluminum silicate with similar doses as that of second & forth
groups. At the end of 8 weeks for each rat, bone marrow was aspirated and
liver was removed for lab examinations. The results showed that rats exposed
to aluminum silicate had severe chromosomal aberrations and changes in CYP
gene expression. It caused significantly increased in the frequency of
chromosomal aberrations such as polyploidy, hypoploidy, deletions,
fragments, chromatid breaks, chromosome breaks, double minutes, ring, gap
and translocation were also observed. Gene expression of CYPs was increased
with exposure to aluminum silicate and was down regulated in treatment with
propolis while Bcl-2 and BAX were decreased in exposure to aluminum silicate
and up regulated by the treatment. Propolis has a curative effect against
aluminum silicate toxicity owing to its antioxidant property.
... They use it as an antiseptic in breeder cells, and they mix propolis with wax to distribute a fine varnish over every inch of the hive to protect it. Chemical properties of propolis are not only beneficial to bees but have general pharmacological value as a natural mixture (Orsolic, 2010).Several empirical and clinical findings point to the fact that propolis may be more effective against pathogenic microorganisms and envirumental pollutes like Lead ( Al-Qayim et al., 2013a). The propolis has been used in folk medicine for antioxidant, immune-stimulating, anti -inflammatory and nontoxic natures ( Cole et al., 2010;Hendi et al., 2011) Propolis has also been found to have powerful anti-inflammatory properties .Propolis can counteract the damaging effects of aluminium( Mahmoud et al., 2013). ...
... It is used in the construction of, and to seal the cracks in, the bee hive. Chemical properties of propolis are not only beneficial to bees but have general pharmacological value as a natural mixture [42]. It is a mixture of resins, essential oils and waxes, and also contains amino acids, minerals, ethanol, vitamins A, B complex, E, and flavonoids [7]. ...
Radioprotection with natural products may be relevant to the mitigation of ionizing
radiation-induced damage in mammalian systems. This study was designed to investigate antioxidant
activity of honey and propolis in vitro through determination of total phenol (TP), total flavonoid (TF)
and free radical scavenging activity (RSA). In addition to, in an in vivo study, male rats were exposed
to fractionated dose gamma irradiation (1 Gy every day up to 5 Gy total doses). Honey and propolis
were administered at dose 250 and 90 mg·kg–1·day–1. The serum levels of alanine transaminase (ALT)
and aspartate transaminase (AST), urea, creatinine and total antioxidants capacity were estimated.
Also hemoglobin of rats was investigated through UV absorption spectrum and dielectric
measurements. The results indicated that total flavonoid, total phenol and free radical scavenging
activity of propolis were greater than honey. AST, ALT, creatinine and urea significantly increased
while total antioxidants significantly decreased after irradiation. Moreover, the absolute values of
permittivity ε', dielectric loss ε'' and ac-conductivity σac increased in addition to a pronounced
decrease in the absorbance at Soret band after irradiation compared to control group. Administration
of propolis induced a significant recovery of antioxidant balance in rats exposed to ionizing radiation.
Indeed, decrease of AST, ALT, creatinine and urea levels decreased in these animals while total
antioxidants significantly increased. Also, the values of ε', ε'' and σac were nearly close to those of the
control group compared to those treated with honey. Finally, the average value of peak height of Soret
band was significantly increased compared to irradiated rat. It can be concluded that propolis can be
more effective than honey in the protection against oxidative damage induced by ionizing radiation.
Further investigations are required to elucidate the mechanisms of propolis and honey actions.
... LDH, BUN, and creatinine are commonly used as markers in the analysis of kidney injury (38). High BUN and serum creatinine levels indicate 5-FU-induced kidney damage. ...
and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FUinduced
hepatotoxicity and nephrotoxicity.
Materials and Methods: Thirty rodents were assigned to three groups. The control group received
1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for
14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered
intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of
naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further
five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken.
Results: It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as
cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared
to the control group. The comparative values were similar in the control and naringin+5-FU groups.
When the liver tissue was examined histopathologically, in the control group it was found to be normal
in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU
group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and
naringin+5-FU groups.
Conclusion: Naringin was observed to have a protective effect on 5-FU-induced liver and kidney
damage.
... LDH, BUN, and creatinine are commonly used as markers in the analysis of kidney injury (38). High BUN and serum creatinine levels indicate 5-FU-induced kidney damage. ...
... 33 This occurs by modulating the expression of growth factors such as VEGF and TNF. 34 Studies, carried out on the antitumor activity of propolis, 35 showed an antiproliferative effect against tumor lines (blood, colon, breast, prostate, lung, liver, brain, kidney). 36 Various studies showed that propolis alcohol extract was able to modulate the expression and activity of factors involved in the carcinogenesis process. ...
... A number of plant-derived natural products have been described as potential alternative therapies for metastatic cancers [10,11]. It has been reported that more than 50% of all modern drugs in clinical use are natural products, many of which exhibit a range of activities including the down-regulation of growth factors (EGF and VEGF), alterations of survival signaling (ERK, JNK, AP-1, and NF-κB), cell cycle regulator proteins (cyclinD1, cdk4/6, p21, and p53), apoptosis regulators (PARP, caspases, Bcl-2 and Bax) and stimulation of immune system responses (IL-1, IL-6, IL-8, TNF-α, macrophages and Natural Killer) [12][13][14]. ...
Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound which has many biological activities as an anticancer agent. The current report is aimed at finding out whether the antitumor potential of chrysin, evidenced in vitro and in vivo, is linked or not to its effect on immunological mechanisms of melanoma-bearing mice.
Chrysin-treated B16F10 cells were analyzed for their metabolic rate and apoptotic potentials. In vivo, BALB/c mice received a subcutaneous injection of B16F10 melanoma cells prior to antitumor treatments with chrysin (50 mg/kg b.w) for 14 days and 21 days.
The results showed that chrysin inhibited cancer cell growth at a dose-dependent manner by inducing apoptosis and cell cycle arrest at G2/M phase. Moreover, chrysin suppressed melanoma tumor growth at an average of 60% (after 14 days of treatment) and 71% (after 21 days of treatment) compared to the tumor-bearing group. Furthermore, chrysin treatment increased the cytotoxic activity of NK, CTL and macrophages.
The findings showed that chrysin antitumor action on the murine melanoma model was very promising, suggesting that chrysin could be a potentially good candidate for future use in alternative anti-melanoma treatments.
... In vitro studies have shown different sensitivity of tumour cells to propolis due to its chemical composition (Bankova 2005a;Frión-Herrera et al. 2015). Propolis may suppress cancer/precancerous cells proliferation (Oršolić 2010) and induce apoptosis or necrosis depending on its chemical composition. These observations led us to compare two distinct chemically characterised samples: Cuban red propolis (CP) and Brazilian green propolis (BP) on human laryngeal epidermoid carcinoma (HEp-2) cells, investigating their mechanisms of action. ...
Propolis has been used as a traditional remedy for centuries because of its beneficial effects, including anticancer properties. The aim of this study was to compare the cytotoxic mechanism of Cuban red propolis (CP) and Brazilian green propolis (BP) on human laryngeal carcinoma (HEp-2) cells. Cell viability, leakage of lactate dehydrogenase, fluorescence staining, mitochondrial membrane potential (ΔΨm) and the expression of pro/anti-apoptotic genes were assessed. Cell viability and cytotoxic assays suggested a dose-dependent effect of CP and BP extracts with a possible association of intracellular reactive oxygen species production and decreased ΔΨm. Both samples induced apoptosis via activation of TP53, CASP3, BAX, P21 signalling, and downregulation of BCL2 and BCL-XL. CP exerted a higher cytotoxic effect than BP extract. Our findings suggest further investigation of the main components of each propolis sample, what may lead to the development of strategies for the treatment of laryngeal cancer.
... Propolis, a resinous hive product collected by honeybees from parts of plants, buds, and exudates is used to seal holes in honeycombs, smooth internal walls and protect the entrance against intruders (Burdock, 1998). Various biological activities, such as anticancer, antioxidant, anti-inflammatory, antibiotic and antifungal effects have been reported for propolis and its constituents (Marcucci, 1995;Kosalec et al., 2007;Oršolić, 2010). The medical applications of propolis extract have led to an increased interest in its chemical composition, their botanical origins, and their medicinal properties. ...
Propolis, a resinous hive product collected by honeybees from parts of plants, buds, and exudates is used to seal holes in honeycombs, smooth internal walls and protect the entrance against intruders (Burdock, 1998). Various biological activities, such as anticancer, anti-oxidant, anti-inflammatory, antibiotic and antifungal effects have been reported for propolis and its constituents (Marcucci, 1995; Kosalec et al., 2007; Oršolić, 2010). The medical applications of propolis extract have led to an increased interest in its chemical composition, their botanical origins, and their medicinal properties. Polyphenolic compounds have been identified in propolis collected by Apis mellifera. Flavonoids, the main polyphenols in propolis, have been found to be quantitatively or qualitatively variable, depending on species of plants in the vicinity of the hive. Very little is known about the composition of chemicals and biological properties of propolis form Canada. Therefore, propolis collected from different geographical regions of Canada was considered to be a promising source of biologically active substances deserving of further investigation.
... Our results indicate that additional cell death induction probably due to the different compositions and proportions [17]. According to [67], propolis and a variety of polyphenolic/flavonoid compounds can influence a number of key intracellular targets that are associated with the cancer process and can serve as regulators of gene expression and/or modulate gene products. New studies on gene expression modulation by these propolis extracts are necessary to understand the physiological reasons for the observed effects on fish leucocytes. ...
Propolis has been used as a medicinal agent for centuries. The chemical composition of four propolis samples collected from four locations of the Sétif region, Algeria, using gas chromatography-mass spectrometry was determined. More than 20 compounds and from 30 to 35 compounds were identified in the aqueous and ethanolic extracts, respectively. Furthermore, the antimicrobial activity of the propolis extracts against two marine pathogenic bacteria was evaluated. Finally, the in vitro effects of propolis on gilthead seabream (Sparus aurata L.) leucocyte activities were measured. The bactericidal activity of ethanolic extracts was very high against Shewanella putrefaciens, average against Photobacterium damselae and very low against Vibrio harveyi. The lowest bactericidal activity was always that found for the aqueous extracts. When the viability of gilthead seabream head-kidney leucocytes was measured after 30 min' incubation with the different extracts, both the ethanolic and aqueous extracts of one of the propolis samples (from Babor) and the aqueous extract of another (from Ain-Abbassa) provoked a significant decrease in cell viability when used at concentrations of 100 and 200 μg ml⁻¹. Furthermore, significant inhibitory effects were recorded on leucocyte respiratory burst activity when isolated leucocytes where preincubated with the extracts. This effect was dose-dependent in all cases except when extracts from a third propolis sample (from Boutaleb) were used. Our findings suggest that some of Algerian propolis extracts have bactericidal activity against important bacterial pathogens in seabream and significantly modulate in vitro leucocyte activities, confirming their potential as a source of new natural biocides and/or immunomodulators in aquaculture practice.
... Propolis or bee glue, a resinous hive product collected by honey bees from parts of plants, buds, and exudates is used to seal holes in honey combs, smooth internal walls and protect the hive entrance against intruders (Burdock, 1998). Various biological activities, such as anticancer, anti-oxidant, anti-inflammatory, antibiotic and antifungal effects have been reported for propolis and its constituents (Kosalec et al., 2007;Marcucci, 1995;Oršolić, 2010). The medical applications of propolis extract have led to an increased interest in its chemical composition, their botanical origins, and their medicinal properties. ...
Propolis is a multifunctional material collected and used by honey bees in the construction and maintenance of their hives. It has been used in folk medicine for centuries. Concentrations of major constituents and antioxidant characteristics of ethanolic extracts of three samples of propolis (EEPs) collected from different geographical locations in Canada (Saskatchewan, Ontario and British Columbia) were determined. Twenty-one compounds were identified in each EEP, of which 18 were polyphenols. Semi-quantitative measurements showed that benzyl caffeate, pinocembrin, sakuranetin and pinobanksin-3-acetate were most abundant in propolis from Ontario. Total phenolic content of EEPs were quantified by using the Folin–Ciocalteu reagent which ranged between 410.81 and 429.61 mg GAE/g EEP. Free radical scavenging activities of propolis were confirmed by use of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and by using Nrf2 Luciferase reporter cell lines. The three EEPs exhibited strong scavenging of free radicals, and protective activity against oxidative stress caused by exposure to H2O2 in this in vitro system. These results support the use of propolis from these regions of Canada as a source of natural antioxidants.
... Moreover, flavonoids from propolis play a protective role against the toxicity of the chemotherapeutic agents or radiation in mice, giving hope that they may have similar protective action in humans. The combination with an adjuvant antioxidant therapy may enhance the effectiveness of chemotherapy by ameliorating the side effect on leukocytes, liver and kidneys and consequently enabling dose escalation 213 The cytotoxic effects leading to the anticancer activity have been reviewed in 2011 by Watanabe et al. 310 Vit et al, 2015, reviews the different properties of propolis which lead to anticancer activity: antioxidant, antiproliferating, cancer cells apoptosis causing, anti-angiogenic (multi-step process to form blood vessels, this process is disturbed in cancer), immuno-supressive, anti-inflamation, immunomodulatory 307 Although many polyphenols have a anti-metastatic activity, caffeic acid phenethyl ester (CAPE) from poplar propolis and Artepillin C from baccharis propolis have been identified as the most potent antitummor agents 5,21,24,214,215,268 , but antitumor effects of chrysin (poplar propolis) and both nemorosone and plukenetione A (in Cuban prropolis) have been reported 307 Consumption of propolis supplement can have a suppressive effect against mutation induced cancer 247 ...
... In fact, propolis avonoids, as effective scavengers of free radicals and other reactive species in vitro, may explain a decrease in oxidative DNA damage in vivo. 33 So, antigenotoxicity and genotoxicity were observed in both pre- Fig. 2 Antigenotoxicity of C.EE in S. cerevisiae cells exposed to oxidative stress (A and C) and genotoxicity of C.EE in S. cerevisiae cells (B and D). Yeast spheroplasts were pre-treated with C.EE (25 mg mL À1 , 100 mg mL À1 or 300 mg mL À1 ) for 20 min, washed with S buffer and incubated with 10 mM H 2 O 2 (A) or S buffer (B) for further 20 min. ...
Propolis is a resinous product made by honeybees from plant-derived materials, with high content of polyphenols associated to several beneficial bioactivities with potential use as a natural food additive for preservation and as a functional food ingredient. A Portuguese propolis ethanol extract (C.EE) protected Saccharomyces cerevisiae cells from loss of viability upon exposure to H2O2, both in co- and in pre-incubation experiments. Results obtained with the comet assay suggest that lower concentrations are antigenotoxic while at higher concentrations a genotoxic effect prevails, which correlates with the cytotoxicity of high concentrations of C.EE. Flow cytometry analysis with dichlorofluorescein indicates that C.EE induced intracellular antioxidant activity in vivo. Overall the results suggest that C.EE is antigenotoxic but is also toxic at higher concentrations. This dual effect could be explained by the presence of compounds known to interfere with DNA synthesis and/or cell proliferation, such as caffeic acid phenethyl ester (CAPE) and chrysin, together with antioxidants, like kaempferol, pinobanksin and pinocembrin.
... However, GSI, gonadal weight and relative gonadal fecundity in the treated groups did not vary from that in the control. It has been suggested that the therapeutic activities of propolis depend mainly on the presence of flavenoids (Marcucci, 1995) that modulate steroid hormones (phytoestrogen activity) and consequently hormone-dependent ovarian activity (Oršolić, 2010) through their capacity to interact with estrogen receptors-ß (Matsumoto et al., 2004) in the reproductive organs. After propolis treatment, a gradual reduction in the mortality of fish eggs in vitro (1.2-2% compared to untreated eggs) has been emphasized (Velotto et al., 2010). ...
... The anti-cancer activities of propolis have been presented in various culture cell lines, such as mammary carcinoma (MCA), human epithelial carcinoma (HeLa), human leukemia (HL-60, CI41, U937), human ovarian carcinoma (SK-OV-3), human lung carcinoma (NCI-H358), human hepatocellular carcinoma (HepG2), human cervical cancer (ME180) and human pancreatic cancer (PANC-1, BxPC-3) cells (Chen et al., 2008). Also, propolis and its polyphenolic compounds exerted considerable cytotoxicity, without cross-resistance, in both wild-type and chemo-resistant human tumor cell lines besides an anti-metastatic and antitumor effect in mice and rats (Orsolic, 2010). Also CAPE-induced apoptosis in HL-60 cells was associated with GSH depletion and scavenging of hydrogen peroxide (Chen et al., 2007). ...
It has been shown previously that nutritional supplements rich in polyphenolic compounds play a significant role in prostate cancer chemoprevention. Propolis is a natural, resinous hive product that has several pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and antitumoral activities. The aim of this study was to compare the cytotoxic, antioxidant and antitumoral activities of an ethanolic extract of Egyptian propolis (EEP) in vitro with an established chemotherapeutic drug such as doxorubicin (DOX), and the effects of their combination against the PC3 human prostate cancer cell line. Cellular viability and IC50 levels with EEP, DOX and their (v/v) combination were detected by sulphorhodamine-B (SRB) assay after incubation of PC3 cells for 72h with different doses (0, 0.01, 0.1, 1, 10 and 100μg/ml). Two selected doses of IC50 and IC25 were applied to cells for 24h for antitumor evaluation assay of treatment compounds. EEP and its (v/v) combination with DOX showed significant antitumor potential besides high antioxidant properties of superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase (CAT), nitric oxide (NO) and reduced glutathione (GSH) levels when compared with the control untreated cells. DNA fragmentation assay and semi quantitative RT-PCR analyses for p53 and Bax genes showed that EEP activated cellular apoptosis and increased the mRNA expression levels more than other treatment. In conclusion, EEP alone or in combination with DOX at both doses used here showed greater antioxidant, antiproliferative and apoptotic effects against the PC3 cell lines as compared to treatment with DOX alone. Therefore, EEP could be considered as a promising candidate for prostate cancer chemotherapy.
... Therefore, these findings suggest that the over-expression of Xiap may cooperate with the induction of necrosis and thereby further contribute to RCP-45 necrotic cell death. According to Orsolic [31] , propolis and a variety of polyphenolic/flavonoid compounds can influence a number of key intracellular targets that are associated with the cancer process and can serve as regulators of gene expression and/or modulate gene products. ...
Propolis is a resin formed by a complex mixture of chemical substances that bees collect from plants.
Since ancient times, propolis has been used in folk medicine due to its biological properties that
include antimicrobial, antioxidant, anti-inflammatory, and antitumoral activities. The aim of this
study was to compare the in-vitro cytotoxic activities of 16 Cuban propolis extracts of different
chemical types: brown (1, 4, 5, 16, and 17 BCP), red (9, 29, 35, 37, 45 and 72 RCP) and yellow (18,
39, 41, 50 and 60 YCP) against murine breast carcinoma F3II, human breast adenocarcinoma MDAMB-
231, human lung adenocarcinoma A549, and human fibroblast MRC-5. These cells were
incubated with different concentrations of propolis and 72 hours after, the IC50 was calculated for
each cell. The results showed the antiproliferative effect of Cuban propolis against all cell lines
tested. RCP was the most interesting group because they did not affect normal cells. RCP-45 extract
showed the highest selectivity index (SI>2) toward A549 compared with MRC-5.In addition, this
extract induced necrosis and caused an increase in mRNA levels of Xiap in A549 cell after 8 h of
treatment. These results could be related tothe classification of Cuban propolis, which is highly
dependent onchemical composition. Our results indicate that Cuban propolis represents an interesting
natural source for anticancer treatment.
Cancer is the second most life-threatening disease and has become a global health and economic problem worldwide. Due to the multifactorial nature of cancer, its pathophysiology is not completely understood so far, which makes it hard to treat. The current therapeutic strategies for cancer lack the efficacy due to the emergence of drug resistance and the toxic side effects associated with the treatment. Therefore, the search for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Propolis is a mixture of resinous compounds containing beeswax and partially digested exudates from plants leaves and buds. Its chemical composition varies widely depending on the bee species, geographic location, plant species, and weather conditions. Since ancient times, propolis has been used in many conditions and aliments for its healing properties. Propolis has well-known therapeutic actions including antioxidative, antimicrobial, anti-inflammatory, and anticancer properties. In recent years, extensive in vitro and in vivo studies have suggested that propolis possesses properties against several types of cancers. The present review highlights the recent progress made on the molecular targets and signaling pathways involved in the anticancer activities of propolis. Propolis exerts anticancer effects primarily by inhibiting cancer cell proliferation, inducing apoptosis through regulating various signaling pathways and arresting the tumor cell cycle, inducing autophagy, epigenetic modulations, and further inhibiting the invasion and metastasis of tumors. Propolis targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, β-catenin, ERK1/2, MAPK, and NF-κB. Possible synergistic actions of a combination therapy of propolis with existing chemotherapies are also discussed in this review. Overall, propolis, by acting on diverse mechanisms simultaneously, can be considered to be a promising, multi-targeting, multi-pathways anticancer agent for the treatment of various types of cancers.
Me olemme kaikki tarinan arvoisia, mutta erityisen tärkeä on sellainen tarina, joka koskettaa monia, tuttuja ja tuntemattomia. Tässä kirjassa saamme kuulla Antti Oinaksen tarinan. Terveystoimittaja Christer Sundqvist on kirjannut muistiin Antin tarinan ja kuljettaa meitä kirjan sivuilla sellaista terveyspolkua pitkin, joka vie terveyttä kohti. Terveyspolku vie meidät positiivisuuden kautta emäksiseen laaksoon, jossa vehreys ja erityisesti koivun antimet tuovat meille elinvoimaa. Sokeria tällä polulla ei ole tarjolla, mutta makeaa on havaita hapen parantava teho. Liikunta on lääke ja lukuisat apuaineet, -menetelmät sekä -laitteet pitävät meidät tarvittaessa kaidalla polulla koko elämän. Vakavasti sairastuneen on syytä ottaa selvää sairaudestaan niin, että hänestä tulee oman sairautensa huippuasiantuntija. Lukuisissa lempeissä keskusteluissa terveydenhoidon ammattilaisten kanssa Antti luo pohjan sille, että terveyspolulla voidaan kiitollisena ottaa vastaan koululääketieteen tarjoama paras mahdollinen apu. Kulman takana saattaa odottaa tieteellinen läpimurto.
Introducción: El propóleo es la sustancia que protege a la colmena, es una resina de composición compleja y viscosa que las abejas utilizan en la reparación y protección de la colmena. El material del que procede el propóleo son las resinas, brotes y pecíolos de las hojas de diferentes vegetales, por ello presenta una composición química muy compleja que varía en función de la flora de recolección de las abejas. Posee capacidad antimicrobiana, antiinflamatoria que está relacionada con su poder antioxidante, inmunomoduladora, entre otras. Objetivos: En este trabajo se estudian las actividades antioxidantes y antitumorales de propóleos de distintas zonas de la provincia de Málaga comparándolos con uno de la región de Bohemia al sur de la República Checa. Material y métodos: La actividad antioxidante se evaluó según el método ABTS+/S2O8K2. Además se estimó la cantidad de proteínas totales a partir del contenido de nitrógeno y posteriormente se determinó la citotoxicidad y actividad antitumoral del propóleo del Puerto de la Torre, al norte de Málaga, según el método del bromuro de 3-(4,5-dimetiltiazol-2-il)-2,5-difenil tetrazolio. Resultados: Se observó que el propóleo presenta una elevada actividad antioxidante, aunque tiene una menor cantidad de proteínas. El propóleo presenta elevada toxicidad y mayor actividad antitumoral frente al cáncer de colon que al de leucemia. Conclusión: Con todos estos datos obtenidos se puede concluir que el propóleo presenta diferentes actividades de interés para la industria alimentaria o cosmética, entre las que destaca su elevado poder antioxidante y su capacidad como antitumoral.
Background:
Breast cancer is a female malignancy that is a significant cause of mortality worldwide. Currently, investigations on natural ingredients as new candidates for chemopreventive agents and breast cancer chemotherapies are increasing. Propolis is a natural resinous material produced by honeybees that exhibit anticancer potential. Several studies have mentioned the major bioactive compounds of propolis, but their mechanism of action is not clearly understood.
Objectives:
The purpose of this review is to collect and summarize the evidence related to the effectiveness of propolis and its bioactive contents as candidates for breast cancer therapy and analyze the molecular mechanisms involved in their therapeutic pathways.
Methods:
We reviewed 94 articles from journals and databases, extracted the results, and produced summaries and conclusions.
Results:
Propolis and its bioactive ingredients show cytotoxic, anti-proliferative, pro-autophagic, anti-metastatic, and antioxidant activities, as well as synergistic effects with chemotherapy or radiotherapy in breast cancer. Its therapeutic activity involves various target molecules, including NF-κβ, Fas receptors, p53, TLR4, ANXA7, and voltage-gated Na+ channel (VGSC).
Conclusion:
The bioactive components of propolis and the target molecules involved need to be explored further to develop new breast cancer therapies and overcome the problem of chemoradiation resistance.
Nutrition is an important factor that influences bone metabolism, the endocrine and/or paracrine system, and bone-active mineral elements homeostasis. We studied antiosteoporotic effects of grape seed proanthocyanidins extract, icariin or alendronate (ALN) in retinoic acid-induced (13cRA) bone loss in rats. Proanthocyanidins and icariin have beneficial effects on bone health; they have improved the bone weight reduction, the length and the diameter of the bone, calcium, and phosphorus content in bone ash, bone mineral density (BMD), the biochemical markers of bone turnover and uterus atrophy induced by 13cRA. All results suggest that proanthocyanidins and icariin reverse osteoporosis in 13cRA rats by stimulating bone formation or regulating bone resorption by their antioxidative and estrogenic-like activity without toxic side-effects observed in ALN treatment.
Objetivos:
La diabetes mellitus es señalada como una de las principales amenazas para la salud humana en el siglo XXI. Entre las plantas medicinales utilizadas tradicionalmente para su tratamiento, se encuentra la Bauhinia forficata que crece en Argentina y Brasil. En este trabajo se realizó un estudio comparativo de parámetros reológicos y fisicoquímicos entre diferentes extractos acuosos obtenidos a partir de hojas de Bauhinia forficata recolectadas en la ciudad de Rosario (Argentina) y hojas comerciales vendidas en dietéticas y farmacias.
Métodos:
Se prepararon soluciones extractivas a partir de las hojas disecadas y solución fisiológica, utilizando los siguientes procedimientos: Cocimiento, Digestión Controlada, Infusión y Maceración. Se realizó la caracterización reológica, óptica y fisicoquímica de los mismos.
Resultados y Conclusiones:
Los resultados obtenidos son de utilidad para el análisis de la hemocompatibilidad de estos extractos, contribuyendo además a los estudios para la comprensión de sus mecanismos de acción como antidiabéticos en fitomedicina.
Introduction:
Propolis is the substance that protects the hive, a resin of complex and viscous composition bees use in the repair and protection of the hive. The material from which propolis arises are the resins, shoots and petioles of the leaves of different plants, so it has a very complex chemical composition that varies depending on the flora of the bees collection. It offers an antimicrobial, anti-inflammatory capacity related to its antioxidant, immunomodulatory power, among others.
Aims:
In this work, antioxidant and antitumoral activities of different propolis collected from different areas of the province of Malaga, comparing them with one from the Bohemian region to the south of the Czech Republic are studied.
Material and methods:
Antioxidant activity was determined according to the ABTS+/S2O8K2 method. In addition, the quantity of total proteins from the nitrogen content and subsequently the cytotoxicity and antitumoral activity of the propolis of Puerto de la Torre, north of Malaga, are measured according to the 3-(4,5-dimetiltiazol-2-il)-2,5-diphenyl tetrazolium bromide method.
Results:
It was observed that propolis has high antioxidant activity, although it has a lower amount of proteins. Propolis has high toxicity and higher antitumoral activity against colon cancer than leukemia.
Discussion:
With all these data, it can be concluded that propolis offers different activities of interest, for the food and cosmetic industry, among which the high antioxidant and antitumoral capacity.
p>Reactive oxygen species (ROS) play a role in a numbered of degenerative conditions including psoriasis. Psoriasis is a chronic inflammatory disease who’s the etiopathogenesis is not yet completely understood, and therefore there is no standardized therapeutical approach. Flavonoids, recognized as potent antioxidants, are multifunctional molecules that can act as anti-inflammatory and antiproliferative agents through the modulation of multiple signaling pathways. The present study was designed to investigate the protective role of flavonoids [quercetin, chrysin, curcumin or Epigallocatechin 3-gallate (EGCG)] against n-Hexyl salicylate (HXS)-induced oxidative stress and inflammation in skin. Anti-oxidative and anti-inflammatory effect of flavonoids is quantified by histopathological assessment of skin, measuring the levels of lipid peroxidation and glutathione (GSH) in the skin, total number of inflammatory cells in peritoneal cavity, macrophage spreading index, and hematological and biochemical parameters.
Topically applied of n-Hexyl salicylate caused significant increase in lipid peroxidation and decrease in GSH, which is accompanied by an increase total number of inflammatory cells in skin and peritoneal cavity, functional activity of macrophages, and enzymatic activity of ALP and AST. In contrast, topically applied 5 % preparation of flavonoids (quercetin, chrysin, curcumin or EGCG) with HXS effectively prevented these alterations and maintained the antioxidant status.
The results suggest that flavonoid preparations can serve as a potent antioxidant and anti-inflammatory agents in psoriatic-like skin lesions, without toxic effects.</p
Summery
Propolis is consist of various amounts of resins and beeswaxes that produced by the honeybees from different natural plants, as leaf buds and flowers. They have been used in medical folk or medical traditional since times of ancient. The medical application of propolis, clinically, as a natural dental medicine in the different dental specialities like oral hygiene, periodontology and oral mucosa pathologies, oral surgery, orthodontics, restorative dentistry; endodontics and prosthetic dentistry. Propolis (bee glue) is used as treated the oral diseases in terms of antimicrobial activity of propolis associate with flavonoids and hydroxyl cinnamic acid, and lower associated risks. The dentistry application of propolis is probably the more well scientifically documented and now applied practically in many countries, commonly, the propolis is applied in the different dental specialties as periodontology, oral mucosa pathology, oral surgery, orthodontics and prosthodontics. Traditional uses of propolis probably has been more commonly used in wood preservatives or varnishes. Propolis is used for Musical instruments by most stringed instrument maker to enhance the appearance of the wood grain. Agriculture indication of propolis increases of weight gain, development rate and productivity of different animals.
Summery
Propolis is consist of various amounts of resins and beeswaxes that produced by the honeybees from different natural plants, as leaf buds and flowers. They have been used in medical folk or medical traditional since times of ancient. The medical application of propolis, clinically, as a natural dental medicine in the different dental specialities like oral hygiene, periodontology and oral mucosa pathologies, oral surgery, orthodontics, restorative dentistry; endodontics and prosthetic dentistry. Propolis (bee glue) is used as treated the oral diseases in terms of antimicrobial activity of propolis associate with flavonoids and hydroxyl cinnamic acid, and lower associated risks. The dentistry application of propolis is probably the more well scientifically documented and now applied practically in many countries, commonly, the propolis is applied in the different dental specialties as periodontology, oral mucosa pathology, oral surgery, orthodontics and prosthodontics. Traditional uses of propolis probably has been more commonly used in wood preservatives or varnishes. Propolis is used for Musical instruments by most stringed instrument maker to enhance the appearance of the wood grain. Agriculture indication of propolis increases of weight gain, development rate and productivity of different animals.
Summery
Propolis is consist of various amounts of resins and beeswaxes that produced by the honeybees from different natural plants, as leaf buds and flowers. They have been used in medical folk or medical traditional since times of ancient. The medical application of propolis, clinically, as a natural dental medicine in the different dental specialities like oral hygiene, periodontology and oral mucosa pathologies, oral surgery, orthodontics, restorative dentistry; endodontics and prosthetic dentistry. Propolis (bee glue) is used as treated the oral diseases in terms of antimicrobial activity of propolis associate with flavonoids and hydroxyl cinnamic acid, and lower associated risks. The dentistry application of propolis is probably the more well scientifically documented and now applied practically in many countries, commonly, the propolis is applied in the different dental specialties as periodontology, oral mucosa pathology, oral surgery, orthodontics and prosthodontics. Traditional uses of propolis probably has been more commonly used in wood preservatives or varnishes. Propolis is used for Musical instruments by most stringed instrument maker to enhance the appearance of the wood grain. Agriculture indication of propolis increases of weight gain, development rate and productivity of different animals.
Summery
Propolis is consist of various amounts of resins and beeswaxes that produced by the honeybees from different natural plants, as leaf buds and flowers. They have been used in medical folk or medical traditional since times of ancient. The medical application of propolis, clinically, as a natural dental medicine in the different dental specialities like oral hygiene, periodontology and oral mucosa pathologies, oral surgery, orthodontics, restorative dentistry; endodontics and prosthetic dentistry. Propolis (bee glue) is used as treated the oral diseases in terms of antimicrobial activity of propolis associate with flavonoids and hydroxyl cinnamic acid, and lower associated risks. The dentistry application of propolis is probably the more well scientifically documented and now applied practically in many countries, commonly, the propolis is applied in the different dental specialties as periodontology, oral mucosa pathology, oral surgery, orthodontics and prosthodontics. Traditional uses of propolis probably has been more commonly used in wood preservatives or varnishes. Propolis is used for Musical instruments by most stringed instrument maker to enhance the appearance of the wood grain. Agriculture indication of propolis increases of weight gain, development rate and productivity of different animals.
This study was conducted to evaluate the interactions between the gut microbiota, ochratoxin A and functional food such as honey and quercetin, and the consequences of these interactions on ochratoxin-induced DNA damage in blood, liver and kidney cells. Honey (2 g kg⁻¹) or Quercetin (50 mg kg⁻¹) was applied to mice by intragastric application every day for 15 days, immediately before ochratoxin treatment (100 µg kg⁻¹). We investigated colonic probiotic bacteria count, β-glucuronidase activity, the alkaline comet assay in blood, liver and kidney, the number of cells in the peritoneal cavity, macrophage spreading index and hematological and biochemical parameters. Honey and QU may reduce ochratoxin-induced DNA damage in the liver and kidney, β-glucuronidase activity and inflammation, partly through increasing the colon Bifidobacteria and Lactobacilli counts. The obtained results suggest that honey and QU counteracted the OTA-induced toxicity due to their bifidogenic activity and antigenotoxic activity.
Macrophage polarization is a process when macrophage expresses different functional programs in response to microenvironmental signals and two extreme forms exist; M1 and M2 macrophages. M1 macrophages are highly microbicidal and anticancer with enhanced ability to kill and phagocytose pathogens, upregulate pro-inflammatory cytokines and reactive molecular species, and present antigens; M2 macrophages and the related tumour associated macrophages (TAMs) regulate tissue remodelling and promote tissue repair and angiogenesis and can amplification of metabolic pathways that can suppress adaptive immune responses. It is demonstrated that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAMs differentiation and tumorigenesis in mouse models of cancer. In order to study how caffeic acid (CA), a natural antioxidant, affects macrophage function, polarization, angiogenesis and tumour growth we injected mice with Ehrlich ascites tumour (EAT) cells and treated them for 10 days with CA in a dose of 40 and/or 80 mg kg−1. Macrophage polarization was further characterized by quantifying secreted pro- and anti-inflammatory cytokines, nitric oxide and arginase 1 activity. CA may increase the cytotoxic actions of M1 macrophages and inhibit tumour growth; inhibitory activity on TAMs may be mediated through its antioxidative activity. Taken together, we conclude that the antitumour activity of CA was the result of the synergistic activities of different mechanisms by which CA acts on proliferation, angiogenesis, immunomodulation and survival. The continuous administration of CA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by antioxidans can be a potentially effective method for cancer treatment.
Interest to develop new anticancer drugs and to design combination treatments with little or
no secondary effects provides new scope for traditional phytochemicals in chemoprevention
and therapy. Propolis is a known source of polyphenols, and flavonoids found in them have
been widely studied as biochemical markers for botanical origin and in explaining their
antioxidant capacity as a key factor in chemoprevention. Antimicrobial, anti-inflammatory
and anticancer biological activities of propolis are known. Studies of cancer cells to measure
the anticancer effect of propolis are designed with one carefully chosen component, and with
extracts applied to cells in culture media. The antitumor effect of propolis and caffeic acid
phenethyl ester (CAPE), bioactive compound of propolis extract, is seen to be associated with its
ability to initiate apoptosis of cancer cells. Chrysin is a flavonoid of interest to identify
signaling molecules related to cancer. As cancer cells develop multidrug resistance (MDR)
during chemotherapy, this opens a new avenue of research on cellular mechanisms of
propolis components in combined treatments designed to overcome MDR.
Export Date: 18 October 2014
Propolis contains a variety of polyphenolic compounds. We investigated the effect of a water-soluble derivatives of propolis (WSDP) and polyphenolic compounds, components of propolis, on growth of Ehrlich ascites tumour (EAT) in mice. Tumour in peritoneal cavity was produced by 2×10 EAT cells. WSDP and polyphenolic compounds (caffeic acid-CA, caffeic acid phenethyl ester-CAPE and quercetin-QU) were given to mice perorally (po). It was found that the volume of ascitic fluid induced by EAT cells and total number of cells present in the peritoneal cavity was markedly reduced in EAT-bearing mice treated with test components and the survival time of treated mice was prolonged. Inhibition of EAT growth was due to their effect on the immune system of mice. When innate and acquired immune responses were evaluated, a dose-related increase of cytotoxic T-cell, NK and B cells activity was observed in test components-treated mice. Furthermore, exposure of animals to test components increased functional activity of macrophages to produce factors regulating the function of B-, T-, and NK- cells respectively. In conclusion, these findings imply that the antitumour activity of WSDP and polyphenolic compounds of propolis enhanced host resistance in the EAT tumour model, increasing the activities of macrophages, cytotoxic T cells, B cells and NK cells.
We investigated the effects of water-soluble derivative of propolis (WSDP), caffeic acid, honey, royal jelly and bee venom on tumour development and metastasis in murine tumour models. Transplantable murine tumours were used: a spontaneous mammary carcinoma (MCa) and a methylcholanthrene–induced fibrosarcoma (FS) of CBA mouse. Metastases in the lung were generated by injecting 105 or 2 × 105 viable tumour cells intravenously. Tumours in the hind leg were generated by subcutaneous injection of 104 or 105 mammary carcinoma cells. Oral application of WSDP or caffeic acid significantly reduced subcutaneous tumour growth and prolonged survival of mice. Honey also exerted a pronounced antimetastatic effect (p < 0.01 or p < 0.001) when applied before tumour cell inoculation (2 g kg−1 orally once a day for 10 consecutive days). Royal jelly did not affect the formation of metastases when given intraperitoneally or subcutaneously. However, synchronous application of tumour cells and royal jelly intravenously significantly (p < 0.001) inhibited the formation of metastases. When bee venom was injected intratumourally, tumours decreased in size. These findings demonstrated that honey-bee products given orally or systemically may have an important role controlling tumour growth and metastasis. Copyright © 2004 Society of Chemical Industry
We determined if soy isoflavones have dose-related estrogenic and methylation effects. Thirty-four healthy premenopausal women were randomized to 40 mg or 140 mg isoflavones daily through one menstrual cycle. Breast specific and systemic estrogenic effects were assessed measuring the estrogenic marker complement (C)3 and changes in cytology, whereas methylation assessment of 5 cancer related genes (p16, RASSF1A, RARbeta2, ER, and CCND2) was performed on intraductal specimens. Serum genistein significantly increased after consuming both isoflavone doses. Cytology did not significantly change at either isoflavone dose. Serum C3 levels posttreatment were inversely related to change in serum genistein (r =-0.76, P = 0.0045) in women consuming low but not high dose isoflavones. The RAR beta 2 hypermethylation increase posttreatment correlated with the posttreatment genistein level considering the entire group (r = 0.67, P = 0.0017) and those receiving high-dose isoflavones (r = 0.68, P = 0.021). At the low but not the high isoflavone dose, CCND2 hypermethylation increase correlated with posttreatment genistein levels (r = 0.79, P = 0.011). In summary, the inverse correlation between C3 and genistein suggests an antiestrogenic effect. Isoflavones induced dose-specific changes in RARbeta2 and CCND2 gene methylation, which correlated with genistein levels. This work provides novel insights into estrogenic and methylation effects of dietary isoflavones.
The zeta chain-associated 70-kDa protein (ZAP-70) of tyrosine kinase plays a critical role in T cell receptor-mediated signal transduction and the immune response. A high level of ZAP-70 expression is observed in leukemia, which suggests ZAP-70 as a logical target for immunomodulatory therapies. (-)-Epigallocatechin gallate (EGCG) is one of the major green tea catechins that is suggested to have a role as a preventive agent in cancer, obesity, diabetes, and cardiovascular disease. Here we identified ZAP-70 as an important and novel molecular target of EGCG in leukemia cells. ZAP-70 and EGCG displayed high binding affinity (Kd = 0.6207 micromol/liter), and additional results revealed that EGCG effectively suppressed ZAP-70, linker for the activation of T cells, phospholipase Cgamma1, extracellular signaling-regulated kinase, and MAPK kinase activities in CD3-activated T cell leukemia. Furthermore, the activation of activator protein-1 and interleukin-2 induced by CD3 was dose-dependently inhibited by EGCG treatment. Notably, EGCG dose-dependently induced caspase-mediated apoptosis in P116.cl39 ZAP-70-expressing leukemia cells, whereas P116 ZAP-70-deficient cells were resistant to EGCG treatment. Molecular docking studies, supported by site-directed mutagenesis experiments, showed that EGCG could form a series of intermolecular hydrogen bonds and hydrophobic interactions within the ATP binding domain, which may contribute to the stability of the ZAP-70-EGCG complex. Overall, these results strongly indicated that ZAP-70 activity was inhibited specifically by EGCG, which contributed to suppressing the CD3-mediated T cell-induced pathways in leukemia cells.
Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phospholipase C gamma 1, ex vivo prostaglandin (PG) E2, cyclooxygenase, and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus noninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also significantly suppressed the colon tumor volume by > 57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%) and levels of PGE2 (> 38%). The formation of prostaglandins such as PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.
Genistein is a dietary-derived plant product that inhibits the activity of protein-tyrosine kinases. We show here that it is a potent inhibitor of the mammalian facilitative hexose transporter GLUT1. In human HL-60 cells, which express GLUT1, genistein inhibited the transport of dehydroascorbic acid, deoxyglucose, and methylglucose in a dose-dependent manner. Transport was not affected by daidzein, an inactive genistein analog that does not inhibit protein-tyrosine kinase activity, or by the general protein kinase inhibitor staurosporine. Genistein inhibited the uptake of deoxyglucose and dehydroascorbic acid in Chinese hamster ovary (CHO) cells overexpressing GLUT1 in a similar dose-dependent manner. Genistein also inhibited the uptake of deoxyglucose in human erythrocytes indicating that its effect on glucose transporter function is cell-independent. The inhibitory action of genistein on transport was instantaneous, with no additional effect observed in cells preincubated with it for various periods of time. Genistein did not alter the uptake of leucine by HL-60 cells, indicating that its inhibitory effect was specific for the glucose transporters. The inhibitory effect of genistein was of the competitive type, with a Ki of approximately 12 microM for inhibition of the transport of both methylglucose and deoxyglucose. Binding studies showed that genistein inhibited glucose-displaceable binding of cytochalasin B to GLUT1 in erythrocyte ghosts in a competitive manner, with a Ki of 7 microM. These data indicate that genistein inhibits the transport of dehydroascorbic acid and hexoses by directly interacting with the hexose transporter GLUT1 and interfering with its transport activity, rather than as a consequence of its known ability to inhibit protein-tyrosine kinases. These observations indicate that some of the many effects of genistein on cellular physiology may be related to its ability to disrupt the normal cellular flux of substrates through GLUT1, a hexose transporter universally expressed in cells, and is responsible for the basal uptake of glucose.
Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate through induction of cell death by apoptosis. This study tested the hypothesis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of tumor promoters. The present study was designed to investigate whether the chemopreventive properties of sulindac, curcumin, and phenylethyl-3-methylcaffeate (PEMC) and the tumor-promoting activity of 6-phenylhexyl isothiocyanate (PHITC) that were observed in our previous studies are associated with the induction or inhibition of apoptosis in azoxymethane (AOM)-induced colon tumors in male F344 rats. At 5 weeks of age, groups of rats were fed control (modified AIN-76A) diet or diets containing 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, or 640 ppm of PHITC. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given AOM (15 mg/kg body weight) once weekly for 2 weeks. To study the effect of sulindac administered during promotion/progression stage, the rats were fed the control diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment. The rats were sacrificed 52 weeks after carcinogen treatment, and their colonic tumors were subjected to histopathological evaluation and the appearance of apoptosis. In the current study, chronic administration of sulindac, curcumin, and PEMC or sulindac given only during promotion/progression significantly increased the apoptotic index (percentage of apoptosis) as compared to administration of the control diet; the apoptotic indices in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during promotion/progression stage, the apoptotic index was 19.1%. However, dietary PHITC blocked the process of apoptosis during colon carcinogenesis. The apoptotic index in PHITC diet was 7.0%. Taken together, our data show that chemopreventive properties of agents are correlated with the degree of apoptosis. Therefore apoptosis seems to be a reliable biomarker for the evaluation of potential agents for cancer prevention.
Plant flavonoids are common dietary components that have many potent biological properties. Early studies of these compounds investigated their mutagenic and genotoxic activity in a number of in vitro assays. Recently, a renewed interest in flavonoids has been fueled by the antioxidant and estrogenic effects ascribed to them. This has led to their proposed use as anticarcinogens and cardioprotective agents, prompting a dramatic increase in their consumption as dietary supplements. Unfortunately, the potentially toxic effects of excessive flavonoid intake are largely ignored. At higher doses, flavonoids may act as mutagens, pro-oxidants that generate free radicals, and as inhibitors of key enzymes involved in hormone metabolism. Thus, in high doses, the adverse effects of flavonoids may outweigh their beneficial ones, and caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet. The unborn fetus may be especially at risk, since flavonoids readily cross the placenta. More research on the toxicological properties of flavonoids is warranted given their increasing levels of consumption.
Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular endothelial cell proliferation, migration, and capillary formation are stimulated by angiogenic growth factors, which include the proteins vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta, and eicosanoids synthesized from n-6 fatty acids. Clinical studies have shown that angiogenesis in solid tumors relates to a poor prognosis and, in premalignant lesions, indicates potential for cancerous transformation. High-fat, n-6 fatty acid-rich diets were associated with a relatively poor prognosis in breast cancer patients; in a nude mouse model the same diet enhanced breast cancer progression, whereas n-3 fatty acids exerted suppressive effects that were associated with impaired angiogenesis. Lipoxygenase and cyclooxygenase products of n-6 fatty acid metabolism are angiogenic in in vitro assays. This activity is blocked by pharmacological inhibitors of eicosanoid biosynthesis, and one, indomethacin, suppressed n-6 fatty acid-stimulated murine mammary carcinoma growth and metastasis and tumor vascularization. Review of the experimental data suggests that selective inhibitors of eicosanoid-synthesizing enzymes and dietary intervention with n-3 fatty acids merit clinical evaluation as adjuvant therapy and chemopreventive agents.
Some cocoas and chocolates are rich in (-)-epicatechin and its related oligomers, the procyanidins. Fractions of these compounds, isolated from the seeds of Theobroma cacao, caused dose-dependent inhibition of isolated rabbit 15-lipoxygenase-1 with the larger oligomers being more active; the decamer fraction revealed an IC50 of 0.8 microM. Among the monomeric flavanols, epigallocatechin gallate (IC50 = 4 microM) and epicatechin gallate (5 microM) were more potent than (-)-epicatechin (IC50 = 60 microM). (-)-Epicatechin and procyanidin nonamer also inhibited the formation of 15-hydroxy-eicosatetraenoic acid from arachidonic acid in rabbit smooth muscle cells transfected with human 15-lipoxygenase-1. In contrast, inhibition of the lipoxygenase pathway in J774A.1 cells transfected with porcine leukocyte-type 12-lipoxygenase (another representative of the 12/15-lipoxygenase family) was only observed upon sonication of the cells, suggesting a membrane barrier for flavanols in these cells. Moreover, epicatechin (IC50 approx. 15 microM) and the procyanidin decamer inhibited recombinant human platelet 12-lipoxygenase. These observations suggest general lipoxygenase-inhibitory potency of flavanols and procyanidins that may contribute to their putative beneficial effects on the cardiovascular system in man. Thus, they may provide a plausible explanation for recent literature reports indicating that procyanidins decrease the leukotriene/prostacyclin ratio in humans and human aortic endothelial cells.
Flavonoids may be partly responsible for some health benefits, including antiinflammatory action and a decreased tendency for the blood to clot. An acute dose of flavanols and oligomeric procyanidins from cocoa powder inhibits platelet activation and function over 6 h in humans.
This study sought to evaluate whether 28 d of supplementation with cocoa flavanols and related procyanidin oligomers would modulate human platelet reactivity and primary hemostasis and reduce oxidative markers in vivo.
Thirty-two healthy subjects were assigned to consume active (234 mg cocoa flavanols and procyanidins/d) or placebo (< or = 6 mg cocoa flavanols and procyanidins/d) tablets in a blinded parallel-designed study. Platelet function was determined by measuring platelet aggregation, ATP release, and expression of activation-dependent platelet antigens by using flow cytometry. Plasma was analyzed for oxidation markers and antioxidant status.
Plasma concentrations of epicatechin and catechin in the active group increased by 81% and 28%, respectively, during the intervention period. The active group had significantly lower P selectin expression and significantly lower ADP-induced aggregation and collagen-induced aggregation than did the placebo group. Plasma ascorbic acid concentrations were significantly higher in the active than in the placebo group (P < 0.05), whereas plasma oxidation markers and antioxidant status did not change in either group.
Cocoa flavanol and procyanidin supplementation for 28 d significantly increased plasma epicatechin and catechin concentrations and significantly decreased platelet function. These data support the results of acute studies that used higher doses of cocoa flavanols and procyanidins.
Animal and epidemiological studies reveal that consuming food and beverages rich in polyphenols (e.g., catechins, flavones, and antocyanines) is associated with a lower incidence of cancer, and several molecular mechanisms have been proposed for explaining this effect. However, because most of these mechanisms were observed only under specific and nonphysiological conditions, and in most cases, with practically irrelevant concentrations, there is still no clear-cut or universal explanation for the major events that underlie the anticancer effects of polyphenols. In this study we present clear in vitro and in vivo evidence that the inhibition of the cancer-associated enzyme telomerase is a key mechanism involved in cancer inhibition by epigallocatechin gallate (EGCG), a major tea polyphenol. We demonstrate that EGCG and other selected polyphenols undergo structural rearrangements at physiologically permissible conditions that result in remarkably increased telomerase inhibition. In nude mice models bearing both telomerase-dependent and -independent xenograft tumors cloned from a single human cancer progeny, only the telomerase-dependent tumors responded to prolonged oral administration of EGCG. Thus, EGCG and likely other structurally related dietary polyphenols seem to act as prodrug-like molecules that, once ingested and distributed, undergo structural changes that favor potent activity against telomerase.
Background and Purpose: Honey has been used as a folly remedy for various ailments, but its heterogeneous composition has limited scientific evaluation of this material. It has been reported that honey possesses moderate antitumor and pronounced antimetastatic effects in murine tumor models. We investigated the antimetastatic efficiency of honey and possible ode of antitumor action. Material and Methods: Transplantable marine tumors were used: a spontaneous mammary carcinoma (MCa) and a methylcholanthrene-induced fibrosarcoma (FS) of CBA mouse and an anaplastic colon adenocarcinoma (ACa) of Y59 rat. Metastases in the lung were generated by injecting viable tumor cells intravenously (iv). Results: A pronounced antimetastatic effect (p < 0.01; 0.001) was achieved by oral application of honey given before tumor cell inoculation (2 gr/kg for mice or 1 gr/kg for rats, once a day for 10 consecutive days); however; given after tumor cell inoculation, honey enhanced lung metastases. Conclusion: These findings indicate that honey activates immune system and may be advantageous with respect to cancer and metastasis prevention. In addition, honey given orally before tumor cell inoculation may have an impact on tumor spread.
Objective. This study was designed to evaluate the anti-angiogenic effect of silymarin (SM) and its major pure component silibinin (SB), and also thalidomide (TH). Materials and methods. A modified in vitro system using a coculture of endothelial (EA.hy 926) and colon cancer (LoVo) cell lines was adopted in this study. Results. In cytotoxicity assay, SM/SB/TH concentrations causing 20% (IC20) inhibition of cellular growth were 41.8 mug/ml/0.22 mM/0.088 mM for EA.hy 926 cells, and 16.1 mug/ml/0.12 mM/0.099 mM for LoVo cells, respectively. All 3 drugs showed concentration dependent inhibition of migration and differentiation assay. The IC50 inhibiting chemotaxis migration of EA.hy 926 towards LoVo by SM/SB/TH was 1.15 mug/ml/0.66 muM/1.98 muM, respectively. In differentiation assay, SM/SB/TH inhibited in vitro capillary tube formation by 50% at 1.25 mug/ml/2.6 muM/6.3 muM, respectively. In an analysis of vascular endothelial growth factor secreted by LoVo cells, SM/SB/TH decreased 50% secretion at 6.52 mug/ml/6.6 muM/131.7 muM, respectively. Conclusion. SM/SB has a strong anti-angiogenesis effect on the colon cancer cell line, and this might provide an alternative treatment option for anticancer treatment.
Background and Purpose: Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) are phenolic antioxidants and active antitumor components of propolis. We aimed to determine the effects of CA, CAPE and water-soluble derivatives of propolis (WSDP) on colony growth, apoptosis, and redox state of HeLa human cervical carcinoma and Chinese hamster lung V79 fibroblast cells. Material and Methods: WSDP, CA and CAPE were used in this study and their cytotoxic effect on HeLa and V79 cells were studied. Colony formation assay and the annexin V method with detection of a hypodiploid cell population by flow cytometry were used for identification of cell growth and apoptosis, respectively. Results: CA and CAPE, but not WSDP, significantly suppressed colony growth. This effect was more pronounced against malignant HeLa cells than against normal V79 cells. CA and CAPE induced apoptosis of HeLa but not of V79 cells. Finally, glutathione levels in V79 cells were unaffected by the tested compounds, whereas they were significantly reduced in HeLa cells. Conclusion: These results suggest that CA and CAPE preferentially affect the growth of malignant cells and that they can modulate the redox state of tumor cells, causing apoptosis.
Background and Purpose: It has been reported that bee venom exhibits antitumor activity in vitro. The aim of this study was to investigate potential antimetastatic and in vivo antitumor activity of the bee venom. Materials and Methods: Bee venom (from "Medex"Ljubljana, Slovenia) was collected utilizing the electric shock method. Its antitumor activity was examined on a transplantable spontaneous mammary carcinoma (MCa) in CBA mice in vivo, and HeLa and V79 cell lines in vitro. Results: Bee venom showed an antitumor effect depending on concentration and on route of injection in vivo and inhibited cell growth and clonogenicity in vitro. The strongest inhibitory effect in vitro was on the V79 cell line. Conclusions: An antitumor effect of the bee venom was established in vivo and in vitro. Apoptosis, necrosis and lysis of the tumor cells were found to be the possible mechanisms by which bee venom inhibited tumor growth.
Caffeic acid phenethyl ester (CAPE), an the active component of propolis, is known to have anticarcinogenic, antiviral and various biological activities; however, the effect of CAPE on the immunomodulatory activity in vivo remains unknown. We have investigated the effect of CAPE on the immune system in female Balb/c mice. CAPE (0, 5, 10, 20 mg/kg) was given to mice orally for 14 days. Immunomodulatory activity was evaluated by assessment of body and organ weight, lymphocyte blastogenesis, plaque-forming cell (PFC) assay, lymphocyte subpopulation by flow cytometry and cytokine production. Even though the change of body weight was not observed in CAPE-administered group, thymus weight and/or cellularity of thymus and spleen are decreased at the all dose groups of CAPE (5, 10, 20 mg/kg). On the other hand, CAPE had no effect on B lymphocyte proliferation induced by lipopolysaccharide (LPS) but increased T lymphocyte blastogenesis induced by concanavalin A (Con A) at the dose of 20 mg/kg. In the case of lymphocyte subpopulation, the population of T and B cells was not changed but CD4(+) T cell subsets are significantly increased in exposure to CAPE. The antibody responses to T lymphocyte dependent antigen, sheep red blood cell and keyhole limpet hemocyanin (KLH) were increased more than 10 mg/kg in CAPE-treated group. Likewise, the cytokine, IL-2, IL-4 and IFN-gamma were significantly increased at the dose of 20 mg/kg CAPE group. These results suggest that CAPE could have immunomodulatory effects in vivo.
Propolis has been the subject of several recent studies, with the aim of elucidating its biological and pharmacological properties. Propolis has a well-known antimicrobial activity as well as antioxidant, antitumoral, antiinflammatory, and regenerative properties, but literature about its effects on the immune response is scarce. The goal of this work was to evaluate the propolis effect on macrophage activation by oxygen (H2O2) and nitrogen (NO) metabolite determination. Propolis was produced by africanized honeybees and hydroalcoholic solutions were prepared at different concentrations. Peritoneal macrophages were obtained from male BALB/c mice and culture cells were stimulated in vitro with propolis or interferon-gamma (IFN-gamma). In the in vivo assay, the animals were sacrificed after propolis treatment and cells were stimulated with IFN-gamma. We also investigated the co-stimulant action of propolis associated with IFN-gamma on macrophages. The results show that propolis induces a discreet elevation in H2O2 release and a mild inhibition of NO generation, depending on concentration. Propolis had no co-stimulant activity, diminishing IFN-gamma action on H2O2 and NO production. Data suggest that propolis acts on host non-specific immunity by macrophage activation.
In order to study a possible immunomodulatory effect of the royal jelly (RJ) secreted by mandibular and hypopharingeal glands of the worker honeybee (Apis mellifera Linne.) we have used a well established rodent model. The CBA mice were given s.c. 0.1 ml of RJ, 7 days before, or immediately after, the immunization with sheep red blood cells (SRBC). The Y59 rats received i.m. 0.4 ml or i.v. 0.025 ml of RJ once or twice at 7 day intervals. Serum levels of total proteins and immunoglobulins in the rats that received RJ once or twice within a 2-week-period were significantly lower (P ≤ 0.05) as compared with the nontreated animals. In mice which were immunized with 4 x 108 of SRBC 7 days after the application of RJ the number of plaque forming splenocytes was significantly higher (P ≤ 0.05) than that in the controls. Both the weight of inguinal lymph node and the number of peripheral blood lymphocytes were increased (P ≤ 0.05) in RJ-treated mice 3 or 5 days after the immunization, respectively. Neutrophils were decreased (P ≤ 0.05) in the mice that were killed 5 or 10 days after the RJ treatment. Overall these results indicate that RJ exhibited immunomodulatory properties by stimulating antibody production and immunocompetent cell proliferation in mice or depressing humoral immune functions in rats. Both phenomena, though species-related in this model, could probably be reversed by changing the dose or the route of RJ application.
Epidemiological studies have described the beneficial effects of dietary polyphenols (flavonoids) on the reduction of the risk of chronic diseases, including cancer. Moreover, it has been shown that flavonoids, such as quercetin in apples, epigallocatechin-3-gallate in green tea and genistein in soya, induce apoptosis. This programmed cell death plays a critical role in physiological functions, but there is underlying dysregulation of apoptosis in numerous pathological situations such as Parkinson's disease, Alzheimer's disease and cancer. At the molecular level, flavonoids have been reported to modulate a number of key elements in cellular signal transduction pathways linked to the apoptotic process (caspases and bcl-2 genes), but that regulation and induction of apoptosis are unclear. The aim of this review is to provide insights into the molecular basis of the potential chemopreventive activities of representative flavonoids, with emphasis on their ability to control intracellular signaling cascades responsible for regulating apoptosis, a relevant target in cancer-preventive approach.
Benzyl isothiocyanate and phenethyl isothiocyanate, two aromatic phytochemicals present in substantial concentrations in edible vegetables of the genus Brassica, were investigated for their effects on Caco-2 cell proliferation. Benzyl and phenethyl isothiocyanate inhibited DNA synthesis, with 50% inhibitory concentrations of 5.1 and 2.4 micromol/L, respectively, and significantly increased the doubling times of Caco-2 cells from 32 h to 220 and 120 h, respectively. There was no adverse effect of either chemical on cell viability in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, but benzyl isothiocyanate and phenethyl isothiocyanate both caused an accumulation of cells in the G(2)/M phase of the cell cycle, which was maintained for at least 48 h in cells synchronized at prometaphase with nocodazole and subsequently treated with 10 micromol/L benzyl isothiocyanate or phenethyl isothiocyanate. Both benzyl and phenethyl isothiocyanate increased DNA strand breakage, increased phosphorylation of the G(2)/M checkpoint enforcer Chk2, and induced p21 expression. These results suggest that the antiproliferative effects of benzyl and phenethyl isothiocyanates toward Caco-2 cells are due at least in part to the activation of the G(2)/M DNA damage checkpoint, and that sustained G(2)/M phase cell cycle arrest in response to benzyl and phenethyl isothiocyanates may be maintained through upregulation of p21. This study indicates that some dietary isothiocyanates may exert an antiproliferative effect through activation of the G(2)/M DNA damage checkpoint.
In this study, cytotoxic effects of structurally related flavones and flavonols on a human esophageal squamous cell carcinoma cell line (KYSE-510) were determined, and the molecular mechanisms responsible for their cytotoxic effects were studied. The results of MTT assay showed that flavones (luteolin, apigenin, chrysin) and flavonols (quercetin, kaempferol, myricetin) were able to induce cytotoxicity in KYSE-510 cells in a dose- and time-dependent manner, and the cytotoxic potency of these compounds was in the order of: luteolin>quercetin>chrysin>kaempferol>apigenin>myricetin. Flow cytometry and DNA fragmentation analysis indicated that the cytotoxicity induced by flavones and flavonols was mediated by G(2)/M cell cycle arrest and apoptosis. Furthermore, the expression of genes related to cell cycle arrest and apoptosis was assessed by oligonucleotide microarray, real-time RT-PCR and Western blot. It was shown that the treatment of KYSE-510 cells with these compounds caused G(2)/M arrest through up-regulation of p21(waf1) and down-regulation of cyclin B1 at the mRNA and protein levels, and induced p53-independent mitochondrial-mediated apoptosis through up-regulation of PIG3 and cleavage of caspase-9 and caspase-3. The results of western blot analysis further showed that increases of p63 and p73 protein translation or stability might be contributed to the regulation of p21(waf1), cyclin B1 and PIG3.
The effect of propolis [it is a water-soluble derivative (WSDP)] and related polyphenolic compounds of propolis (caffeic acid, caffeic acid phenethyl ester and quercetin), honey, royal jelly and bee venom on tumour growth, metastasizing ability and induction of apoptosis and necrosis in murine tumour models (mammary carcinoma and colon carcinoma) was investigated. WSDP and related polyphenolic compounds showed significant anti-metastatic effect (P < 0.01 and P < 0.001) given either before or after tumour-cell inoculation. Oral or systemic application of WSDP or caffeic acid significantly reduced subcutaneous tumour growth and prolonged the survival of mice. Honey also exerted pronounced anti-metastatic effect (P < 0.05) when applied before tumour-cell inoculation (peroral 2 g kg(-1) for mice or 1 g kg(-1) for rats, once a day for 10 consecutive days). Royal jelly did not affect metastasis formation when given intraperitoneally or subcutaneously. However, intravenous administration of royal jelly before tumour-cell inoculation significantly (P < 0.05) inhibited metastasis formation. When mice were given 10(5) tumour cells intravenously immediately after bee venom injection, the number of tumour nodules in the lung was significantly lower (P < 0.001) than in untreated mice or mice treated with bee venom subcutaneously. Local presence of bee venom in the tissue caused significant delay in subcutaneous tumour formation. These findings clearly demonstrate that anti-tumour and anti-metastatic effects of bee venom are highly dependent on the route of injection and on close contact between components of the bee venom and tumour cells. These data show that honey bee products given orally or systemically may have an important role in the control of tumour growth and tumour metastasizing ability.
5-Aza-2'-deoxycytidine (5-AZA-CdR), a potent inhibitor of DNA methylation, is an effective agent for the treatment of leukemia. The aim of this study was to investigate the antileukemic activity of this epigenetic agent in combination with genistein, a nontoxic isoflavone with chemopreventive activity. The combined treatment produced a synergistic loss of clonogenicity in human myeloid (HL-60) and lymphoid (MOLT-3) leukemic cell lines. Genistein alone showed a significant antileukemic activity against murine 5-AZA-CdR-resistant cells, and this effect was enhanced when used in combination with 5-AZA-CdR. The combined treatment also produced a synergistic increase in life span of mice with L1210 leukemia. These results suggest that genistein may have the potential to increase the clinical efficacy of 5-AZA-CdR for the treatment of leukemia.
(-)-Epigallocatechin gallate (EGCG), the main polyphenolic constituent of green tea, inhibits tumor promotion and chemical carcinogenesis in animal experimental systems. Here we report that the peroral administration of EGCG inhibited metastasis of B16 melanoma cell lines, such as B16-F10 and BL6, in both experimental and spontaneous systems.
We examined the ratio of neutrophils to lymphocytes (N/L ratio) in the peripheral blood in patients with colorectal cancer. The ability to produce active oxygen and phagocytosis of neutrophils, G-CSF, sIL-2R and IAP (immunosuppressive acidic protein) were also measured. The N/L ratios were significantly higher in the advanced stages of cancer than in normal controls. The ability to produce active oxygen in the terminal stage was 33% lower than in the control group. The G-CSF levels had no relationship with the neutrophil counts. IAP levels increased with cancer stage, and were inversely related to the ability to produce active oxygen. The IAP levels correlated well with the sIL-2R levels and the N/L ratio. These findings suggest that the ability to produce active oxygen, N/L ratio and IAP reflect anticancer mechanisms and that they may be useful when considering treatment or prognosis of patients with advanced stages of cancer.
Peroxynitrite is a cytotoxic species generated by the reaction between superoxide and nitric oxide. The ability of catechins and their gallate esters to decrease peroxynitrite-induced nitration of tyrosine and to limit surface charge alteration of low density lipoprotein (LDL) was investigated. All compounds tested were found to be potent peroxynitrite scavengers preventing the nitration of tyrosine. The ability of the catechin polyphenols at 10 microM to minimise tyrosine nitration induced by peroxynitrite (500 microM) was ECG (38.1 +/- 3.6%) approximately EGCG (32.1 +/- 7.5%) approximately gallic acid (32.1 +/- 1.9%) > catechin (23.9 +/- 5.4%) approximately epicatechin (22.9 +/- 3.3%) approximately EGC (19.9 +/- 2.0%). Trolox (10 microM) was used as the standard for comparative purposes and was found to be less effective than the polyphenols in inhibiting tyrosine nitration (13.6 +/- 2.9%). The catechin polyphenols were also found to offer protection from peroxynitrite-induced modification of critical amino acids of apolipoprotein B-100 of LDL which contribute towards its surface charge.
The studies presented were conducted to assess the effect of the soy isoflavone genistein on proliferation of estrogen-independent human breast cancer cells (MDA-MB-231) in vitro and in vivo. Genistein (20 mcmol/L) inhibited cell proliferation in vitro by approximately 50%. Cell cycle progression was blocked in G(2)/M with 40 and 80 mcmol/L genistein. To evaluate the effect of dietary genistein on tumor growth in vivo, genistein was fed to female athymic mice inoculated with MDA-MB-231 cells. After solid tumor masses had formed, mice were fed genistein at a dose (750 mcg/g AIN-93G diet), shown to produce a total plasma genistein concentration of approximately 1 mcmol/L. This dose of genistein did not significantly (P > 0.05) alter tumor growth. Studies were then conducted to assess the effect of dietary genistein on initial tumor development and growth. Genistein (750 mcg/g AIN-93G diet), fed 3 d before cells were inoculated into mice, did not significantly (P > 0.05) inhibit tumor formation or growth. The plasma concentration of genistein in mice fed this dose of dietary genistein (750 mcg/g AIN-93G diet) does not appear sufficient to inhibit tumor formation or growth. Dietary genistein at 750 mcg/g AIN-93G diet does not inhibit tumor formation or growth. Additional studies were conducted to determine the effect of dietary dosages ranging from 0 to 6000 mcg/g AIN-93G diet on plasma genistein concentration. Plasma genistein concentration increased in a dose-dependent manner up to 7 mcmol/L at 6000 mcg/g AIN-93G diet. These data suggest that although genistein inhibits cancer cell growth in vitro, it is unlikely that the plasma concentration required to inhibit cancer cell growth in vivo can be achieved from a dietary dosage of genistein.
We investigated whether resveratrol (RV) affects azoxymethane (AOM)-induced colon carcinogenesis, by administering RV (200 microg/kg/day in drinking water) to male F344 rats for 100 days, beginning 10 days before carcinogen treatment (two weekly doses of 15 mg/kg AOM). Aberrant crypt foci (ACF) were isolated and proliferation, apoptosis and expression of the cell cycle genes bax and p21 were determined. RV significantly reduced the number of ACF/colon [25.7 +/- 3.6 (mean +/- SEM) versus 39.4 +/- 3.3 in controls; P < 0.01] and their multiplicity (2.7 +/- 0.3 versus 4.9 +/- 0.6 in controls; P < 0.01), and also abolished large ACF. In RV-treated rats, bax expression was enhanced in ACF but not in the surrounding mucosa. In both controls and RV-treated rats, proliferation was higher in ACF than in normal mucosa. p21 was expressed in ACF of controls and of RV-treated rats and in normal mucosa of controls, but was lost in normal mucosa of RV-treated animals. In conclusion, the results suggest a protective role of RV in colon carcinogenesis with a mechanism involving changes in bax and p21 expression.