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Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms
Abstract
Ginger has been used throughout the world as spice, food and traditional herb. We found that 6-gingerol, a phenolic alkanone isolated from ginger, enhanced the TRAIL-induced viability reduction of gastric cancer cells while 6-gingerol alone affected viability only slightly. 6-Gingerol facilitated TRAIL-induced apoptosis by increasing TRAIL-induced caspase-3/7 activation. 6-Gingerol was shown to down-regulate the expression of cIAP1, which suppresses caspase-3/7 activity, by inhibiting TRAIL-induced NF-kappaB activation. As 6-shogaol has a chemical structure similar to 6-gingerol, we also assessed the effect of 6-shogaol on the viability of gastric cancer cells. Unlike 6-gingerol, 6-shogaol alone reduced the viability of gastric cancer cells. 6-Shogaol was shown to damage microtubules and induce mitotic arrest. These findings indicate for the first time that in gastric cancer cells, 6-gingerol enhances TRAIL-induced viability reduction by inhibiting TRAIL-induced NF-kappaB activation while 6-shogaol alone reduces viability by damaging microtubules.
... Herbal medicines' use is increasing as compared to the use of chemicals day by day, therefore, more research has been performed on phytochemicals to make them more effective for the intervention of various ailments (Ishiguro et al., 2007). But it is very troublesome to explore the effectiveness of herbal treatment because of the presence of many compounds in various forms (Raynor et al., 2011). ...
... The affliction of gastric cancer is incredibly more in Asia, central and eastern Europe, and Latin America while in most western European countries and North America, it is not a more widespread cancer (Ferro et al., 2014). Studies have shown that 6-gingerol and 6-shogaol, the active components of ginger, are involved in an anticancer activity that shows a different mode of action against gastrointestinal cancer (Ishiguro et al., 2007;Prasad & Tyagi, 2015). Tumor necrosis factor-related apoptosis-inducing ligand (TRIAL) is a cytokine that plays a role in apoptosis and thus is involved in the suppression of metastasis in the host (Thorburn, 2007). ...
... 6-Gingerol upregulates the TRIAL-induced apoptosis by enhancing the TRIAL-induced caspase-3/7 activation. Caspase 3/7 are proteases that are involved in cell death machinery (Ishiguro et al., 2007). 6-gingerol suppresses the activity of inhibitors of caspase-3/7 like cIAP1 and thus promotes cell death (Prasad & Tyagi, 2015). ...
... Herbal medicines' use is increasing as compared to the use of chemicals day by day, therefore, more research has been performed on phytochemicals to make them more effective for the intervention of various ailments (Ishiguro et al., 2007). But it is very troublesome to explore the effectiveness of herbal treatment because of the presence of many compounds in various forms (Raynor et al., 2011). ...
... The affliction of gastric cancer is incredibly more in Asia, central and eastern Europe, and Latin America while in most western European countries and North America, it is not a more widespread cancer (Ferro et al., 2014). Studies have shown that 6-gingerol and 6-shogaol, the active components of ginger, are involved in an anticancer activity that shows a different mode of action against gastrointestinal cancer (Ishiguro et al., 2007;Prasad & Tyagi, 2015). Tumor necrosis factor-related apoptosis-inducing ligand (TRIAL) is a cytokine that plays a role in apoptosis and thus is involved in the suppression of metastasis in the host (Thorburn, 2007). ...
... 6-Gingerol upregulates the TRIAL-induced apoptosis by enhancing the TRIAL-induced caspase-3/7 activation. Caspase 3/7 are proteases that are involved in cell death machinery (Ishiguro et al., 2007). 6-gingerol suppresses the activity of inhibitors of caspase-3/7 like cIAP1 and thus promotes cell death (Prasad & Tyagi, 2015). ...
There is a multitude of life-threatening and widespread health issues worldwide, regarding weak immunity, severe inflammation, viral infections, bacterial infections as well as antimicrobial resistance (AMR), high free radicals generation, and cancer. Ginger, a perennial plant of the Zingiberaceae family with several authentic nutritional and medicinal values used in many countries as traditional medicine. That is why, the study was designed to highlight recent studies about medicinally most efficacious bio-active compounds of ginger along their biological significance related to immuno-stimulatory, anti-inflammatory, anti-viral, anti-bacterial, anti-oxidant, and anti-cancer effects. Our study also recognized future gaps in research. The study included professional research data under duration from 2001-2022 appearing in books and scholarly journals, collected from scientific database platforms via PubMed, Web of Science, Google Scholar, Springer Nature, Science Direct and Scopus. The present study includes the medicinal effects of almost 44 most influential ginger compounds like phenolics, terpenoids, flavonoids, and vinyllyl ketonic compounds etc. Our results revealed the strong alleviating effects of gingerols, shogaols, paradols, and polyphenols. Moreover, the ginger essential oil has proven to be very effective both for antiviral and antibacterial activity. However, no data is available in previous literature for components of ginger involved in immuno-stimulatory, effects. There is also a need to explore components for antibacterial activity. However, research has been conducted on ginger for only a few viruses despite its strong alleviating effects. Besides this, more study is needed to comprehend the comprehensive mechanism of action (especially at the molecular level) regarding the anti-bacterial and anti-viral activity of ginger and its constituents.
... Five studies have studied the anti-inflammatory effects and these papers have shown that treating cells with ginger reduced inflammation (Ishiguro et al., 2007;Ling et al., 2010;Miyoshi et al., 2003;Romero et al., 2018;Saha et al., 2014). Also, four papers have proven that ginger has increased the activity of caspases (Choudhury et al., 2010;Ishiguro et al., 2007;Miyoshi et al., 2003;. ...
... Five studies have studied the anti-inflammatory effects and these papers have shown that treating cells with ginger reduced inflammation (Ishiguro et al., 2007;Ling et al., 2010;Miyoshi et al., 2003;Romero et al., 2018;Saha et al., 2014). Also, four papers have proven that ginger has increased the activity of caspases (Choudhury et al., 2010;Ishiguro et al., 2007;Miyoshi et al., 2003;. All in vitro studies have shown that the treatment of cells with ginger stops their cell growth and causes cell death ( Table 1). ...
... The in vitro studies have shown that the amount of Bcl-2 in the treated cells with ginger has decreased, while Bax protein has increased. In addition, several in vitro studies examined the role of proliferative factors and MMPs (Choudhury et al., 2010;Ishiguro et al., 2007;Ling et al., 2010;Rhode et al., 2007). ...
Ginger and its derivatives have been shown to be effective in the prevention and treatment of cancer. We undertook a systematic review to answer the question of whether ginger has a role in modifying the biomarkers of cancer in cell culture conditions and on colorectal cancer in randomized clinical trials. We performed a comprehensive search of the literature from Scopus, Embase, Web of Science, PubMed, Cochrane central register of controlled trials, and Cochrane database of systematic reviews. At first, all 12 papers studied the effect of ginger or its derivatives on cell culture conditions. The results of cell culture studies show that ginger has a powerful role in inducing apoptosis. In the second part, five studies of clinical trials were analyzed. By analyzing antitumor markers of clinical trials, ginger increased some anticancer markers but performed poorly in inducing some anticancer markers. This systematic review showed that the consumption of ginger extract has the potential to prevent and treat colorectal cancer but this ability is weak. This systematic review showed that the consumption of ginger extract has the potential to prevent and treatment of colorectal cancer but this ability is weak.
... [10] Recent studies showed that 6-gingerol as main component of ginger inhibited nuclear factor kappa B (NF-κB) activation by impairing the nuclear translocation of NF-κB, suppression of cIAP expression and increased trial-induced caspase-3/7 activation in gastric cancer cells. [11] The inhibitory effect of 6-gingerol on proliferation of hepatoma cells has been shown in cell culture. [12] One study suggested that ginger arrested cell cycle and induced apoptosis. ...
... [12] One study suggested that ginger arrested cell cycle and induced apoptosis. [11] Animal studies showed that 6-shogaol prohibited growth of pancreatic cancer and increased the effects of gemcitabine in the suppression of tumor growth. [13,14] Also 6-gingerol induces apoptosis in the prostate cancer cell. ...
... A significant number of in vitro and in vivo studies reported that ginger and its active compounds have anti-cancer effect against GI cancer. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] Apoptosis is a very important process for selective cell removal, which plays a critical role in many cellular processes. Caspases are important factors of the apoptotic system. ...
Aim: Ginger is a natural dietary rhizome with antioxidant, anti-inflammatory, and anticarcinogenic properties. It has many medical beneficial properties such as anti-proliferation and antiapoptotic effects on cancerous esophageal cells. Materials and Methods: Esophageal cancer cells ESO26 were cultured in the presence and absence of ginger extract at various concentrations for 12, 18, and 24h. Then, the viability was determined by 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide (MTT) assay. Western blot analysis of caspase-3 was performed to detect apoptosis. p21, Bax, and Bcl-2 gene expression was measured using quantitative polymerase chain reaction (PCR). Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey test. Results: The ginger extract increased the cleavage of caspase-3 in cells (P 0.05). Results of real-time PCR have shown that ginger decreased the expression of Bcl-2 and increased Bax and p21 gene expression (P 0.05). Conclusions: Results showed that the process of cell proliferation has been stopped. Also, this study indicated that ginger might exert a chemopreventive effect on esophageal cancer through the suppression of proliferation and the growth of tumor cells as well as the induction of apoptosis. © 2020 Journal of Reports in Pharmaceutical Sciences | Published by Wolters Kluwer . Medknow.
... Chung et al. (2009) suggested that zingerone exerts anti-inflammatory action by suppressing NF-κB activity and increasing hepatic nuclear factor-4 and PPARs (Chung et al., 2009). Ishiguro et al. (2007) reported that 6-gingerol and 6-shogaol inhibit the expression of NF-κB and reduce the viability of gastric cancer cells (Ishiguro et al., 2007). Li, Mcgrath, et al. (2012) reported that ginger attenuates hepatic inflammatory responses via downregulating the expression of NF-κB in the liver of rats fed a TA B L E 1 0 The mean ± SEM of zinc in the liver and serum of studied groups* high-fat diet (Li, Mcgrath, et al., 2012). ...
... Chung et al. (2009) suggested that zingerone exerts anti-inflammatory action by suppressing NF-κB activity and increasing hepatic nuclear factor-4 and PPARs (Chung et al., 2009). Ishiguro et al. (2007) reported that 6-gingerol and 6-shogaol inhibit the expression of NF-κB and reduce the viability of gastric cancer cells (Ishiguro et al., 2007). Li, Mcgrath, et al. (2012) reported that ginger attenuates hepatic inflammatory responses via downregulating the expression of NF-κB in the liver of rats fed a TA B L E 1 0 The mean ± SEM of zinc in the liver and serum of studied groups* high-fat diet (Li, Mcgrath, et al., 2012). ...
Abstract
Although studies have shown that ginger, as an herbal remedy and zinc are able to improve inflammation, oxidative stress, autophagy, and metabolism of lipid and glucose, their molecular mechanisms are unknown. Therefore, this study was aimed to examine the therapeutic effects of ginger with zinc supplement for eight weeks on fructose‐induced metabolic syndrome (MS). Ninety‐six adult male Sprague Dawley rats (220 g ± 20) were randomly assigned to twelve controlled and treated groups. After the last treatment session, the level of lipid profiles, glucose, insulin, and leptin as metabolic factors and liver enzymes as biomarkers to evaluate liver function in serum were measured. The level of antioxidant enzymes and lipid peroxidation to evaluate the oxidative status and the TNF‐α level as a biomarker to assess the state of inflammation in liver were also measured. The level of zinc along with the expression of NF‐κB, mTORC1, PPAR‐α, SREBP‐1c, and Nrf2 in liver was also evaluated. The level of metabolic factors and liver enzymes in serum along with lipid peroxidation and TNF‐α in liver increased; zinc and antioxidant enzymes levels decreased in rats with MS compared to control rats (p < .05). The hepatic expression of SREBP‐1c, NF‐κB and mTORC1 were upregulated and the expression of PPAR‐α and Nrf2 were downregulated in rats with MS compared to control rats (p < .05). Treatment with different doses of ginger, zinc, and the combination of them could improve metabolic, inflammatory oxidative stress factors, and expression of the above genes in rats with MS compared to the MS group (p < .05). It can be concluded that ginger, zinc, and the combination of them could improve oxidative damage, inflammation, and autophagy induced by fructose and could adjust the glucose and lipid metabolism and the homeostasis of zinc in rats with MS.
Practical applications
Due to the increasing prevalence of metabolic diseases, the use of plant compounds such as ginger has attracted widespread attention. Ginger as an herbal remedy with predominant pharmacological properties due to its availability, cheapness, and lack of side effects is also very popular for the treatment of metabolic disorders in folk medicine. Moreover, enhancing its medicinal properties with supplements such as zinc can be widely welcomed. This study was actually performed with the aim of investigating the effects of ginger + zinc supplement on MS. The results showed that the ginger + zinc supplement could improve oxidative damage, inflammation, and autophagy caused by fructose and adjust the glucose and lipid metabolism and the homeostasis of zinc in rats with MS. The results of this study support the hypothesis that ginger can be used as a very suitable option for the production of medicinal supplements to maintain human health.
... Ginger is a traditional Chinese medicine that is used for both food and medicine (9). Previous studies have reported that ginger serves an antitumor role in various types of malignant tumors (10)(11)(12)(13)(14)(15)(16)(17). For example, 6-gingerol, the main active component of ginger, can induce the apoptosis of gastric cancer cells via different mechanisms (11). ...
... Previous studies have reported that ginger serves an antitumor role in various types of malignant tumors (10)(11)(12)(13)(14)(15)(16)(17). For example, 6-gingerol, the main active component of ginger, can induce the apoptosis of gastric cancer cells via different mechanisms (11). (6)-gingerol can effectively inhibit colon tumor growth in nude mice (12) and (6)-paradol has antitumor-promoting properties (13). ...
Several chemicals in the environment, particularly those with estrogenic activity and small amounts (micromolar or lower) of environmental estrogen can cause changes in cell function and interfere with endocrine functions of animals and humans. These compounds enter the human body and increase the load of estrogen in the body, leading to an increasing incidence of estrogen-related tumors in breast cancer, ovarian cancer and endometrial cancer. Previous studies have demonstrated that ginger can inhibit the expression of estrogen receptors, while the bioactive ingredients of ginger sig-nificantly inhibit proliferation and promote the apoptosis of breast cancer cells. In the present study, a quantitative proteomics technique based on relative and absolute quanti-tative isobaric labeling was used to determine the effect of ginger essential oil (GEO) and BPA combined treatment on the proteomic characteristics of MCF-7 cells. In total, 5,084 proteins were detected. Proteins that were upregulated >1.2-fold and downregu-lated by >0.8-fold were differentially expressed. Overall, 528 differentially expressed proteins were identified. Compared with the control group, MCF-7 cells treated with GEO, BPA and GEO-BPA resulted in 45 (14 up- and 31 downregulated), 481 (141 up- and 340 downregulated) and 34 (13 up- and 21 downregulated) differentially ex-pressed proteins, respectively. Compared with the BPA group, MCF- 7 cells treated with GEO-BPA resulted in 210 (117 up- and 93 downregulated) differentially expressed proteins, among the 210 differentially expressed proteins in the GEO-BPA group, 10 proteins were associated with oxidative phosphorylation pathways, while succinate dehydrogenase (ubiquinone) iron-sulfur subunit (SDHB), succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC), cytochrome c oxidase subunit 2 and superoxide dismutase (Mn), mitochondrial (SOD2) expression was decreased with GEO-BPA combined treatment. Through the analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, the cellular localization, functional annotation and biological pathways of differentially expressed proteins were ex-amined. The results indicated that GEO-BPA may act through the oxidative phosphory-lation pathway, decreased the expression of SDHB and SDHC, affected the tricarbox-ylic acid cycle and decreased the expression of SOD2. This may have led to oxidative stress and the death of breast cancer cells, and the SDH signaling pathway may be an important mediator of the inhibitory effects of GEO in MCF-7 breast cancer cells. GEO can inhibit the proliferation of breast cancer MCF-7 cells induced by BPA, and the underlying mechanism may be associated with oxidative phosphorylation. These results may aid the development of future treatment strategies for breast cancer caused by environmental estrogen exposure.
... Chung et al. (2009) suggested that zingerone exerts anti-inflammatory action by suppressing NF-κB activity and increasing hepatic nuclear factor-4 and PPARs (Chung et al., 2009). Ishiguro et al. (2007) reported that 6-gingerol and 6-shogaol inhibit the expression of NF-κB and reduce the viability of gastric cancer cells (Ishiguro et al., 2007). Li, Mcgrath, et al. (2012) reported that ginger attenuates hepatic inflammatory responses via downregulating the expression of NF-κB in the liver of rats fed a TA B L E 1 0 The mean ± SEM of zinc in the liver and serum of studied groups* high-fat diet (Li, Mcgrath, et al., 2012). ...
... Chung et al. (2009) suggested that zingerone exerts anti-inflammatory action by suppressing NF-κB activity and increasing hepatic nuclear factor-4 and PPARs (Chung et al., 2009). Ishiguro et al. (2007) reported that 6-gingerol and 6-shogaol inhibit the expression of NF-κB and reduce the viability of gastric cancer cells (Ishiguro et al., 2007). Li, Mcgrath, et al. (2012) reported that ginger attenuates hepatic inflammatory responses via downregulating the expression of NF-κB in the liver of rats fed a TA B L E 1 0 The mean ± SEM of zinc in the liver and serum of studied groups* high-fat diet (Li, Mcgrath, et al., 2012). ...
Although studies have shown that ginger, as an herbal remedy and zinc are able to improve inflammation, oxidative stress, autophagy, and metabolism of lipid and glucose, their molecular mechanisms are unknown. Therefore, this study was aimed to examine the therapeutic effects of ginger with zinc supplement for eight weeks on fructose‐induced metabolic syndrome (MS). Ninety‐six adult male Sprague Dawley rats (220 g ± 20) were randomly assigned to twelve controlled and treated groups. After the last treatment session, the level of lipid profiles, glucose, insulin, and leptin as metabolic factors and liver enzymes as biomarkers to evaluate liver function in serum were measured. The level of antioxidant enzymes and lipid peroxidation to evaluate the oxidative status and the TNF‐α level as a biomarker to assess the state of inflammation in liver were also measured. The level of zinc along with the expression of NF‐κB, mTORC1, PPAR‐α, SREBP‐1c, and Nrf2 in liver was also evaluated. The level of metabolic factors and liver enzymes in serum along with lipid peroxidation and TNF‐α in liver increased; zinc and antioxidant enzymes levels decreased in rats with MS compared to control rats (p < .05). The hepatic expression of SREBP‐1c, NF‐κB and mTORC1 were upregulated and the expression of PPAR‐α and Nrf2 were downregulated in rats with MS compared to control rats (p < .05). Treatment with different doses of ginger, zinc, and the combination of them could improve metabolic, inflammatory oxidative stress factors, and expression of the above genes in rats with MS compared to the MS group (p < .05). It can be concluded that ginger, zinc, and the combination of them could improve oxidative damage, inflammation, and autophagy induced by fructose and could adjust the glucose and lipid metabolism and the homeostasis of zinc in rats with MS.
Practical applications
Due to the increasing prevalence of metabolic diseases, the use of plant compounds such as ginger has attracted widespread attention. Ginger as an herbal remedy with predominant pharmacological properties due to its availability, cheapness, and lack of side effects is also very popular for the treatment of metabolic disorders in folk medicine. Moreover, enhancing its medicinal properties with supplements such as zinc can be widely welcomed. This study was actually performed with the aim of investigating the effects of ginger + zinc supplement on MS. The results showed that the ginger + zinc supplement could improve oxidative damage, inflammation, and autophagy caused by fructose and adjust the glucose and lipid metabolism and the homeostasis of zinc in rats with MS. The results of this study support the hypothesis that ginger can be used as a very suitable option for the production of medicinal supplements to maintain human health.
... Interestingly, 6-Shogaol is a bioactive ingredient in ginger (Zingiber officinale Roscoe) and has anticancer properties against many human cancer cells [30][31][32]. However, up to date, the anticancer effect and mechanism of action of 6-Shogaol in liposarcoma are unknown. ...
... Studies have previously shown that 6-Shogaol has anti-proliferative, anti-survival, and pro-apoptotic effects on many different types of human cancer cells, such as SMMC-7721 (liver), HGC (gastric), A2780 (ovarian), COLO 205 (colon), A549 (lung), HeLa (cervix), and MDA-MB-231 (breast) [30][31][32]39,[41][42][43]. The known molecular mechanisms underlying 6-Shogaol's anticancer effects include the induction of apoptosis, the activation of caspase-9, -8, -3, the accumulation of sub G1 phase cells [30,[42][43][44][45][46], and the arrest of the cell cycle [47]. ...
Notably, 6-Shogaol, a bioactive natural substance, has anticancer effects on many types of tumors. Up to date, the anticancer effect and mode of action of 6-Shogaol on liposarcoma are not known. In this study, we investigated whether 6-Shogaol inhibits the growth of SW872 and 93T449 cells, two different human liposarcoma cell lines. Of note, 6-Shogaol inhibited the growth of SW872 and 93T449 cells without affecting that of normal 3T3-L1 preadipocytes. Specifically, 6-Shogaol further induced the apoptosis of SW872 cells, as evidenced by nuclear DNA fragmentation, increased sub G1 population, activation of the intrinsic caspase pathway, and PARP cleavage. However, pretreatment with either z-VAD-fmk, a pan-caspase inhibitor, or N-acetylcysteine, an antioxidant, attenuated the 6-Shogaol's growth-suppressive and apoptosis-inducing effects on SW872 cells. Moreover, 6-Shogaol activated AMPK while inhibited STAT-3 in SW872 cells, and siRNA-based genetic silencing of AMPK or STAT-3 considerably blocked the growth-suppressive and apoptotic response of 6-Shogaol to SW872 cells. Moreover, 6-Shogaol also upregulated the expression and phosphorylation of GRP-78, eIF-2α, ATF4, and CHOP, known ER stress markers, in SW872 cells, illustrating the induction of ER stress. These findings collectively demonstrate that 6-Shogaol has strong antigrowth and proapoptotic effects on SW872 cells through regulation of the intrinsic caspase pathway, oxidative stress, STAT-3, AMPK, and ER stress.
... 6-gingerol induced apoptosis via cytosolic inhibitor of apoptosis (cIAP)-1 down regulation and blocking trailinduced nuclear factor-kappaB (NF-κB) activation. In addition to 6-gingerol, 6-shogaol also harmed microtubules, which decreased the viability of stomach cancer cells [25] . Ginger extract dramatically decreased the area of the gastric ulcer in Sprague-Dawley rats with ulcers caused by acetic acid. ...
... Anti-cancer Effect Z. officinale exhibits anti-inflammatory and anti-tumorigenic effects due to its bio active molecules such as 6-gingerole, 6-shogaol, 6-paradol and zerumbone, as a result prevention or control from colorectal, gastric ovarian, liver, breast and prostate cancers is possible. [38][39][40][41][42][43][44][45] Z. officinale activates enzymes such as glutathione peroxidase, glutathione s transferase and glutathione reductase and suppress colon carcinogenesis. 46 Oral administration of Zerumbone effects in inhibition of multiplicity of colonic adenocarcinomas through suppression of colonic inflammation due to inhibition of proliferation, induction of apoptosis and suppression of NF-ĸB and heme oxygenase (HO)-1 expression. ...
Ginger, the rhizome of Zingiber officinale, species of the ginger family (Zingiberaceae) has a long history of medicinal use for more than 2000 years as one of the most versatile medicinal plants having a wide spectrum of biological activity and a common condiment for various foods and beverages. Rhizome of Zingiber officinale (ginger) is extensively used in medicinal purpose. Ayurveda literatures highlight administration of ginger in both of communicable and non-communicable diseases. Recent advances in analytical chemistry, cytology and microbiology recommend application of ginger in various disease conditions as well as recommendations in Ayurveda literature. The medicinal properties of ginger are due to the presence of gingerol and paradol, shogaols, etc… Currently, there is a renewed interest in ginger. Therefore, in the current study we aimed to describe and delineate on medicinal activites of Z. officinale including antiviral, anti-inflammatory, antioxidant, cardiovascular, gastrointestinal, and neuroprotective activities.
... Shogaols, a dehydrated product of gingerols, are present in larger amounts in dried ginger but exist in fresh ginger at low levels (Jolad et al., 2005). It is studied that 6-shogaols may reduce gastric cancer viability by impairing tubulin polymerization (Ishiguro et al., 2007) and induce apoptosis via activation of caspase and the production of reactive oxygen species in human colorectal carcinoma cells (Pan et al., 2008). Moreover, 6-shogaols has also been reported inhibit effectively the expression of inflammatory mediators, inducible cyclooxygenase-2 and nitric oxide synthase induced by either lipopolysaccharide or phorbol 12-myristate 13-acetate (PMA) (Pan et al., 2008). ...
Skin cancer is one of the most prevalent cancers worldwide. Some limited therapy methods, including surgery, radiation therapy, and chemotherapy, are performed for squamous cell carcinoma, basal cell carcinoma, and melanoma, as well-known skin cancers. The current treatment methods have a relatively low success rate and may leave different side effects during and after therapy. Therefore, finding alternative methods without side effects to treat skin cancer has always been interesting to oncology researchers. Thus, nutraceuticals and herbal medicines for skin cancer treatment have become particularly important in recent years. In this regard, the main classes of nutraceutical compounds with powerful anticancer potential discussed in this book chapter are included phenolic acids, flavonoids, carotenoids, vitamins, and terpenes.
... In an in vitro research, [6]-gingerol increased caspase-3 and caspase-7 activation and triggered apoptosis in gastric cancer cells. The stimulation of apoptosis was mediated by [6]-gingerol via blocking TRAIL-induced NF-kB activation and downregulating cellular inhibitor of apoptosis 1 (cIAP)-1 (Ishiguro et al. 2007;Prasad and Tyagi 2015). Mahady et al. studied the impact of [6]-, [8]-, and [10]-gingerols on 19 strains of Helicobacter pylori including the most vulnerable type cagA + . ...
The rhizomes of ginger have been in use in many forms of traditional and alternative medicines. Besides being employed as condiment and flavoring agent, it is used in the treatment of nausea, osteoarthritis, muscle pain, menstrual pain, chronic indigestion, Alzheimer’s disease, and cancer. Ginger rhizome contains volatile oils, phenolic compounds and resins, and characterization studies showed that [6]-gingerol, [6]-shogaol, and [6]-paradol are reported to be the pharmacologically active components. Gingerol is a major chemical constituent found as volatile oil in the rhizomes of ginger. It has several medicinal benefits and used for the treatment of rheumatoid arthritis, nausea, cancer, and diabetes. Many studies have been carried out in various parts of the world to isolate and standardize gingerol for their use as a complementary medicine. The present review summarizes wide range of research studies on gingerol and its pharmacological roles in various metabolic diseases.
Graphical Abstract
... Ginger and its phytoconstituents have also been effective against other cancers such as ovarian [158], colon [146], non-small lung [159], lung [159], gastric adenocarcinoma [160], melanoma [161], and cervical [162] by modulating NF-κB, p21, ERK1/2, p38, p53, Wnt/ßcatenin, and AMPK. Gingerols were also found to be effective in preventing emesis caused by chemotherapies [147]. ...
In an attempt to find a potential cure for cancer, scientists have been probing the efficacy of the food we eat and its bioactive components. Over the decades, there has been an exponentially increasing trend of research correlating food and cancer. This review explains the molecular mechanisms by which bioactive food components exhibit anticancer effects in several cancer models. These bioactive compounds are mainly plant based or microbiome based. While plants remain the primary source of these phytochemicals, little is known about probiotics, i.e., microbiome sources, and their relationships with cancer. Thus, the molecular mechanisms underlying the anticancer effect of probiotics are discussed in this review. The principal mode of cell death for most food bioactives is found to be apoptosis. Principal oncogenic signaling axes such as Akt/PI3K, JAK/STAT, and NF-κB seem to be modulated due to these bioactives along with certain novel targets that provide a platform for further oncogenic research. It has been observed that probiotics have an immunomodulatory effect leading to their chemopreventive actions. Various foods exhibit better efficacy as complete extracts than their individual phytochemicals, indicating an orchestrated effect of the food components. Combining bioactive agents with available chemotherapies helps synergize the anticancer action of both to overcome drug resistance. Novel techniques to deliver bioactive agents enhance their therapeutic response. Such combinations and novel approaches are also discussed in this review. Notably, most of the food components that have been studied for cancer have shown their efficacy in vivo. This bolsters the claims of these studies and, thus, provides us with hope of discovering anticancer agents in the food that we eat.
... In vitro studies have shown that ginger has anti-neoplastic and chemopreventive properties for treating gastric cancer. The phenolic compound 6-gingerol, derived from ginger, increases functionally distinct caspase 3 and caspase 7 activation to enhance TRAIL-induced apoptosis (Fig. 4) [78]. It has been reported that TRAIL reduces cytosolic inhibitor of apoptosis (cIAP)-1 expression, suppresses caspase 3/7 activity, and inhibits NF-κB (nuclear factor kappa B) activation. ...
The scientific literature indicates that ginger is known for its medicinal properties from ancient times. Ginger is an excellent source of bio-active compounds. It can stimulate the immune system to protect against various types of cancers. In the review, the bio-active compounds of ginger like gingerols, shogaols, paradols, terpenes, camphene, zingerone, and zingiberene and their role in ameliorating liver, pancreatic, colorectal, and gastric cancer types by inhibiting multiple pathways of carcinogenesis are discussed. Additionally, ginger compound-based nanoparticles have been discussed in terms of cancer therapeutics. Various ginger-derived nanoparticles synthesized employing technology have focused on delivering chemotherapeutic medications into specific cancer cells. Future studies should be an integrative method that uses nature-derived nanoparticles from edible plants to load and release cancer therapy into various malignant tissues, allowing for a faster recovery in people with multiple primary tumors.
... Z. officinale exhibits antiinflammatory and anti-tumorigenic effects due to its bio active molecules such as 6gingerole, 6-shogaol, 6-paradol and zerumbone, as a result prevention or control from colorectal, gastric ovarian, liver, breast and prostate cancers is possible. [32][33][34][35][36][37][38][39] Z. officinale activates enzymes such as glutathione peroxidase, glutathione s transferase and glutathione reductase and suppress colon carcinogenesis. [40] Oral administration of Zerumbone effects in inhibition of multiplicity of colonic adenocarcinomas through suppression of colonic inflammation due to inhibition of proliferation, induction of apoptosis and suppression of NF-ĸB and heme oxygenase (HO)-1 expression. ...
Rhizome of Zingiber officinale (ginger) is extensively used in medicinal purpose. Ayurveda literatures highlight administration of ginger in both of communicable and non-communicable diseases. Recent advances in analytical chemistry, cytology and microbiology recommend application of ginger in various disease conditions as well as recommendations in Ayurveda literature. The current study focused on review ethno medicinal value of Z. officinale including antiviral effect, radioprotective effect, anti-inflammatory effect, anticancer effect and antioxidant effect with special reference to Ayurveda recommendations. The study elaborates; ginger is effective in viral infections and revitalizing the body at disease conditions according to both of Ayurveda and modern concepts through enhancing appetite, immunity and re-boosting weakened physiological functions of the human body. Active ingredients which available in ginger such as 6-gingerole, 6-shogaol, 6-paradol, zingerole and zerumbone are responsible in upgrading enzyme actions and balancing circulation through rejuvenating the body with physical re-strengthening.
... Similar to previous results for COLO 205 cells (137), caspases-3 and -9, BAX and cytochrome c were found to be up-regulated in [6]-shogaoltreated Hep2 cells, following a dose-dependent pattern (138). Other similar pro-oxidant and cytotoxic activities for [6]shogaol were also reported for other cancer subtypes, such as gastric, ovarian, lung and breast cancer (139)(140)(141)(142). ...
Cancer remains the second leading cause of death worldwide. Research is currently focused on finding novel anticancer therapies and elucidating their mechanisms of action. Cellular redox balance is a promising target for new therapies, as cancer cells already have elevated levels of oxidizing agents due to hypermetabolism and genetic instability. Although free radicals are actively involved in vital cellular signaling pathways, they have also been implicated in certain diseases, including cancer. The aim of this review was to highlight the involvement of oxidative stress in the mechanism of action of anticancer agents. The difference in cellular redox balance between normal and cancer cells is discussed as a potential anticancer target, along with various examples of approved or experimental drugs that may alter the redox state. These drugs are presented in relation to their pro-oxidant or antioxidant mechanisms, with the consequent goal of underscoring the importance of such mechanisms in the overall efficacy of anticancer drugs.
... It exhibits antioxidant, anti-platelet, anti-inflammatory, anti-proliferative, and anti-cancer activities (30)(31)(32)(33). 6-Gingerol has been reported to induce anti-tumor activity against breast (28), colorectal (34), gastric (35), and pancreatic cancers (36). However, the mechanism of cell death by 6-gingerol in CSCs is unknown. ...
Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSCs with natural compounds is a promising approach as it suppresses cancer recurrence with fewer adverse effects. 6-Gingerol is an active component of ginger, which exhibits well-known anti-cancer activities. This study determined the mechanistic aspects of cell death induction by 6-gingerol. To analyze cellular processes, we used Western blot and real-time qPCR for molecular signaling studies and conducted flow cytometry. Our results suggested an inhibition of CSC marker expression and Wnt/β-catenin signaling by 6-gingerol in NCCIT and NTERA-2 cells. 6-Gingerol induced reactive oxygen species generation, the DNA damage response, cell cycle arrest, and the intrinsic pathway of apoptosis in embryonic CSCs. Furthermore, 6-gingerol inhibited iron metabolism and induced PTEN, which both played vital roles in the induction of cell death. The activation of PTEN resulted in the inhibition of PD-L1 expression through PI3K/AKT/p53 signaling. The induction of PTEN also mediated the downregulation of microRNAs miR-20b, miR-21, and miR-130b to result in PD-L1 suppression by 6-gingerol. Hence, 6-gingerol may be a promising candidate to target CSCs by regulating PTEN-mediated PD-L1 expression.
... Shogaols have gained interest because of recent discoveries revealing their higher anticancer potencies over gingerols. It is reported that [6]-, [8]-and [10]-gingerols had little to no effect but [6]-shogaol signicantly inhibited the growth of A- [28] [ 87] 2780 ovarian cancer cells . Kim [82] gingerol . ...
Ginger, the rhizome of the Zingiber officinale, has shown therapeutic role in health management since
ancient times and considered as potential chemo-preventive agent in various human diseases. It is widely
used in traditional and Ayurvedic medicines for the treatment and management of various health ailments
including rheumatism, asthma, stroke, constipation, diabetes etc. There are scientific evidences that
ginger may alleviate the symptoms of nausea and vomiting following pregnancy, surgery, cancer therapy
or motion sickness and suggestive evidence that ginger reduces inflammation and pain. Ginger produces
a hot, fragrant kitchen spice and often pickled in vinegar or sherry as a snack or cooked as flavoring
ingredient in many Indian dishes and herbal remedies. Numerous chemical components of ginger have
been reported with their significant biological activities. Phytochemical analysis of ginger showed the
presence of active ingredients such as gingerol, shogoal, zingerone, paradol, zingerberene and other
terpenoids and flavonoids, which are responsible for its various ethnomedical significance and biological
activities. Molecular mechanism of active ingredients for antioxidant, anti-tumour anti-inflammatory,
analgesic, hepatoprotective and anticancerous activities has been involved in induction of apoptosis and
modulation of genes. The main aim to write this review is to give insight on active ingredients of ginger
and their valuable nutritional and pharmacological properties which will help students and researchers
to get the overall information about published nutritive and pharmacological properties of its ingredients.
... 6-shogaol unlike 6-gingerol reduces viability and showed no significant synergy with TRAIL in a caspase 3/7 independent manner. 6shogaol also damaged the microtubules indicating that it induces mitotic arrest in gastric cancer cells [84]. ...
Ginger is one of the most valuable culinary medicinal spice with inestimable economic uses. Because it is, a well acknowledged plant both in folkloric and advanced medicine, there are no paucity of information on the many important uses of ginger in the literature. In this review, we conveyed important details on the chemistry, pharmacology, toxicity and clinical uses of ginger. Our review of over 171 articles showed that ginger use has a worldwide coverage. Randomized clinical trial studies on ginger are most prominent on the alleviation of pregnancy-induced nausea and vomiting with fascinating outcome. In addition, the prospective use as anti-inflammatory, thrombolytic, and anti-diabetic agent were well noticed. Although the dependent on plant as source of drug in the search for disease remedy is premised on their acclaimed effectiveness and safety, available data have showed plants may possess some toxic potential, overall, our review showed that ginger might be safe with no adverse effects when investigated in normal rodent and human. Review Article Adewale et al.; JOCAMR, 15(4): 44-67, 2021; Article no.JOCAMR.72871 45
... Ginger (Zingiber officinale Roscoe) is well known for its pungent flavour and medicinal uses (Ahmed et al., 2021;Kubra and Rao, 2012). Its reported medicinal properties include anti-inflammatory action (Grzanna et al., 2005), antioxidant activity (Siddaraju and Dharmesh, 2007), improving cardiovascular and circulatory health Nurtjahja-Tjendraputra et al., 2003;Thomson et al., 2002), analgesic and anti-pyretic activity (Ojewole, 2006), as well as anti-carcinogenic (Cheng et al., 2011;Ishiguro et al., 2007;Prasad and Tyagi, 2015) and antimicrobial effects (Panpatil et al., 2013;Siddaraju and Dharmesh, 2007). ...
Gingerols and their shogaol derivatives play an important role in determining the sensory and organoleptic properties of ginger. In this study, 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol were quantified in 98 samples of dried Australian processing-grade ginger using high performance liquid chromatography (HPLC). A significant level of variation was found in the gingerol and shogaol contents of ginger samples grown under different conditions. The level of variation found in 6-shogaol content was lower than that observed for 6-gingerol, 8-gingerol or 10-gingerol content. It is possible that zeroth-order reaction kinetics under mild dehydration conditions could be responsible for this observation. More detailed information on the kinetics of the gingerol-dehydration reaction could potentially be used to manipulate the gingerol and shogaol contents of ginger through differential heat treatments.
... 6-Gingerol is considered as the main pharmacological component of ginger as it has anti-oxidant, anti-platelet, anti-inflammatory, anti-proliferative, and anti-cancer activities [10][11][12][13][14][15]. 6-Gingerol has been reported to induce antitumor activity against various types of cancers such as pancreatic [16], gastric [17], colorectal [18], and renal [19]. However, the exact mechanism of cell death by 6-gingerol in breast cancer is yet to be discovered. ...
Hormone-specific anticancer drugs for breast cancer treatment can cause serious side effects. Thus, treatment with natural compounds has been considered a better approach as this minimizes side effects and has multiple targets. 6-Gingerol is an active polyphenol in ginger with various modalities, including anticancer activity, although its mechanism of action remains unknown. Increases in the level of reactive oxygen species (ROS) can lead to DNA damage and the induction of DNA damage response (DDR) mechanism, leading to cell cycle arrest apoptosis and tumorsphere suppression. Epidermal growth factor receptor (EGFR) promotes tumor growth by stimulating signaling of downstream targets that in turn activates tumor protein 53 (p53) to promote apoptosis. Here we assessed the effect of 6-gingerol treatment on MDA-MB-231 and MCF-7 breast cancer cell lines. 6-Gingerol induced cellular and mitochondrial ROS that elevated DDR through ataxia-telangiectasia mutated and p53 activation. 6-Gingerol also induced G0/G1 cell cycle arrest and mitochondrial apoptosis by mediating the BAX/BCL-2 ratio and release of cytochrome c. It also exhibited a suppression ability of tumorsphere formation in breast cancer cells. EGFR/Src/STAT3 signaling was also determined to be responsible for p53 activation and that 6-gingerol induced p53-dependent intrinsic apoptosis in breast cancer cells. Therefore, 6-gingerol may be used as a candidate drug against hormone-dependent breast cancer cells.
... Lee et al. [51] demonstrated that 1-dehydro-10-gingerdione suppressed NF-κB-regulated gene expression through inhibiting the catalytic activity of cell-free IKKβ in lipopolysaccharides-treated macrophages. Moreover, 6-gingerol, a representative active component of ginger, showed anti-inflammatory properties by inhibiting TRAIL-induced NF-κB activation [52]. In our study, administration of acidified ethanol significantly increased NF-κB activation through translocation from cytosol to the nucleus accompanied by expression of pro-inflammatory cytokines. ...
Ginger (Zingiber officianale), the most widely consumed species, is traditionally used as a folk medicine to treat some inflammatory diseases in China and Korea. However, the functional activity of steamed ginger extract on gastric ulcers has not been previously explored. The present study aimed to investigate antiulcer activity of steamed ginger extract (GGE03) against ethanol (EtOH)/HCl-induced gastric ulcers in a rat model. GGE03 (100 mg/kg) was orally administered for 14 days to rats before oral intubation of an EtOH/HCl mixture to induce gastric damage. Pretreatment with GGE03 markedly protected the formation of microscopic pathological damage in the gastric mucosa. Further, administration of GGE03 significantly increased mucosal total nitrate/nitrite production in gastric tissues, and elevated total GSH content, catalase activity and superoxide dismutase (SOD) expression as well as decreasing lipid peroxidation and myeloperoxidase (MPO) activity. Underlying protective mechanisms were examined by assessing inflammation-related genes, including nuclear factor-κB (NF-κB), prostaglandin E2 (PGE2), and pro-inflammatory cytokines levels. GGE03 administration significantly reduced the expression of NF-κB and pro-inflammatory cytokines. Our findings suggest that GGE03 possesses antiulcer activity by attenuating oxidative stress and inflammatory responses.
... Studies have suggested the anti-cancer properties of ginger and its constituents are associated with cell growth inhibition, apoptosis induction, antioxidant, and anti-inflammatory potentials of its active components. In the in vitro studies, both 6-gingerol and 6-shogaol were found to reduce the viability of gastric cancer cells by ligand-induced apoptosis or mitotic arrest (Ishiguro et al., 2007). The anti-proliferation and anti-invasion activities of both components were also well documented against other cancer cells such as cancers of the liver, colon, and rectum , breast , glioma (Rahman et al., 2014), and pancreatic cancer Park et al., 2006). ...
Cancer is a multifaceted disease with different hallmarks. The development procedure of anticancer drugs needs different screening methods and disease models to examine the basic mechanism of action of natural products. At present, more than 60% of anticancer drugs are natural products which are either isolates of plants or their derivatives, indicating the opportunity for new drug development from natural product. The mode of action and targets of different compounds are generally different, leading to a challenge for researcher to elucidate the action and mechanism appropriately. For an anticancer drug development, several experimental procedures are required such as extraction, fractionation, purification, identification and finally evaluation. This procedure is completed through different experimental models and assays such as biochemical characterization, antioxidant assay, anticancer assay, ROS assay, apoptosis assay, cell migration assay, pharmacological assays, computer-based evaluation, etc. The screening and development of anticancer drugs are well discussed in this chapter.
... Studies have suggested the anti-cancer properties of ginger and its constituents are associated with cell growth inhibition, apoptosis induction, antioxidant, and anti-inflammatory potentials of its active components. In the in vitro studies, both 6-gingerol and 6-shogaol were found to reduce the viability of gastric cancer cells by ligand-induced apoptosis or mitotic arrest (Ishiguro et al., 2007). The anti-proliferation and anti-invasion activities of both components were also well documented against other cancer cells such as cancers of the liver, colon, and rectum , breast , glioma (Rahman et al., 2014), and pancreatic cancer Park et al., 2006). ...
... Recent literature shown that the curcumin can induce TRAIL-related programmed cell death in malignant-glioma cells [189]. [6]-Gingerol, ginger extracted phenolic alkanone, facilitation in gastric cancer cells to TRAIL-related apoptosis with enhanced TRAIL-induced caspase-3 [190]. Treatment of TRAIL-resistant A549 cells to a high concentration of sulforaphane mediated TRAIL associated apoptosis [191]. ...
Dietary and environmental factors have been known to affect human health, for good or for bad. Diet plays a crucial role in modulating the disease state in an individual. Among the different chronic diseases, cancer has been the most researched topic due to its wide associations and high mortality rate. Efforts have been made to elucidate molecular mechanisms capable of altering pathways of carcinogenesis. Though chemical drugs have proved their worth as anticancer drugs, the side effects far exceed the benefit they confer. In contrast, plants are considered as the highest source of phytochemicals that offer great potential of acting as an anticarcinogenic agent with minimal side effects. They help in upregulating cytoprotective genes, encoding carcinogenic detoxifying enzymes, and antioxidant enzymes. Higher consumption of berries, vegetables, and whole grains has been associated with reduced cancer risk and other chronic diseases. In general, it has been shown that phytochemicals modulate oncogenic processes by their antioxidant and anti-inflammatory activities and their capacity to replicate the chemical structure and hormone production. Phytochemicals act as anticancer agents that target signaling pathways at different levels, such as transcriptional and post-transcription control, protein activation, and intercellular communication. These compounds have been known to modulate coding as well as non-coding RNAs such as microRNAs and short non-coding RNAs. Other mechanistic pathways for chemoprevention involve the initiation of cell cycle arrest and apoptosis and disruption of signal transduction pathways mainly of mitogen-activated protein kinases, phosphoinositide 3-kinase, protein kinases C, glycogen synthase kinase contributing to pathological cyclooxygenase-2, activator protein-1, nuclear factor kB, and c-myc expression. The Warburg effect is another interesting target for chemotherapeutics. A logical approach for chemoprevention is to address malfunctioning molecules along the compromised signal transduction pathway in cancer. Another crucial chemotherapeutic strategy is to counter the pathways involved in controlling the invasiveness and angiogenesis of tumors. Therefore, cell signaling cascades and their influencing factors have become important targets of chemoprevention, and in this direction the plant extracts are showing promising leads.
... 6-Shogaol has achieved a great attention among other shogaols in terms of its anticancer activity against different neoplasms. For example, in gastric cancer, 6-shogaol induced mitotic arrest and decreased cell viability of actively dividing cells [3]. In HCT-116 colorectal cancer cells, 6-shogaol induced the aberrant mitosis, leading to cells apoptosis [4]. ...
Objectives
Breast cancer is one of the most commonly diagnosed cancer among women globally. Shogaol, the active constituent of many spices belonging to the Zingiberaceae family, has received wide attention among other shogaols in terms of its anticancer activity against different neoplasms. To date, its efficacy at the detailed molecular level against breast cancer has not been established.
Methods
In the current study, we investigated the cytotoxic potential and the underlying molecular details of 6-shogaol against breast adenocarcinomacells (MCF-7), and breast ductal carcinoma cells (T47D). Cytotoxicity assay, cell cycle analysis. Real-time PCR (qPCR), apoptosis and autophagy techniques were used for the determination and molecular investigation of its anticancer properties.
Results
The current study shows that, Notch signaling downregulation (Hes1 and CyclinD1 genes), caused by 6-shogaol, lead to antiproliferative activity in breast cancer cells. The study further shows that treatment with 6-shogaol induced significant and time dependent cell cycle accumulation in G2/M-phase. 6-Shogaol also induced significant apoptosis in breast cancer cells. Interestingly, 6-shogaol inhibited autophagy in breast cancer cell lines, which might force these cells to undergo apoptosis. Conclusion: 6-Shogaol is a promising candidate to be considered as a treatment of breast cancer.
... Z. officinale exhibits antiinflammatory and anti-tumorigenic effects due to its bio active molecules such as 6gingerole, 6-shogaol, 6-paradol and zerumbone, as a result prevention or control from colorectal, gastric ovarian, liver, breast and prostate cancers is possible. [32][33][34][35][36][37][38][39] Z. officinale activates enzymes such as glutathione peroxidase, glutathione s transferase and glutathione reductase and suppress colon carcinogenesis. [40] Oral administration of Zerumbone effects in inhibition of multiplicity of colonic adenocarcinomas through suppression of colonic inflammation due to inhibition of proliferation, induction of apoptosis and suppression of NF-ĸB and heme oxygenase (HO)-1 expression. ...
The rhizome of Zingiber officinale (ginger) is extensively used in medicinal purposes. Ayurveda literature highlights the administration of ginger in both communicable and non-communicable diseases. Recent advances in analytical chemistry, cytology, and microbiology recommend the application of ginger in various disease conditions as well as recommendations in Ayurveda literature. The current study focused on review the ethnomedicinal value of Z. officinale including antiviral effect, radioprotective effect, anti-inflammatory effect, anticancer effect and antioxidant effect with special reference to Ayurveda recommendations. The study elaborates; ginger is effective in viral infections and revitalizing the body at disease conditions according to both Ayurveda and modern concepts through enhancing appetite, immunity and re-boosting weakened physiological functions of the human body. Active ingredients available in ginger such as 6-gingerol, 6-shogaol, 6-paradol, zingerole and zerumbone are responsible for upgrading enzyme actions and balancing circulation through rejuvenating the body with physical re-strengthening.
... An in vivo study pointed out that S-allylmercaptocysteine, one of the garlic derivatives, could suppress the growth of SGC-7901 xenografts in BALB/c nude mice [63]. In addition, 6-shogaol from ginger inhibited the gastric tumor growth in athymic nude mice, and it was also found to inhibit the viability of gastric cancer cells, damage microtubules and induce mitotic arrest [64]. Furthermore, (-)-epigallocatechin gallate (EGCG) inhibited the proliferation of SGC-7901 gastric cancer cells and the growth of gastric tumors in mice by suppressing Wnt/β-catenin signaling [65]. ...
Gastric cancer is the fifth most common cancer, and the third most prevalent cause of cancer-related deaths in the world. Voluminous evidence has demonstrated that phytochemicals play a critical role in the prevention and management of gastric cancer. Most epidemiological investigations indicate that the increased intake of phytochemicals could reduce the risk of gastric cancer. Experimental studies have elucidated the mechanisms of action, including inhibiting cancer cell proliferation, inducing apoptosis and autophagy, and suppressing angiogenesis as well as cancer cell metastasis. These mechanisms have also been related to the inhibition of Helicobacter pylori and the modulation of gut microbiota. In addition, the intake of phytochemicals could enhance the efficacy of anticancer chemotherapeutics. Moreover, clinical studies have illustrated that phytochemicals have the potential for the prevention and the management of gastric cancer in humans. To provide an updated understanding of relationships between phytochemicals and gastric cancer, this review summarizes the effects of phytochemicals on gastric cancer, highlighting the underlying mechanisms. This review could be helpful for guiding the public in preventing gastric cancer through phytochemicals, as well as in developing functional food and drugs for the prevention and treatment of gastric cancer.
... In view of their great biological importance to health, plantderived antioxidants are of great interest and their use is more strongly recommended as a substitute for synthetic antioxidants such as butyl hydroxyanisole (BHA) and butyl hydroxytoluene (BHT) which have been shown to be toxic and carcinogenic [8]. Indeed, gingerol and its derivatives, from ginger, are biomolecules active in the prevention and treatment of gastric and colorectal cancers, prostate and ovaries [9]. In the food industry, their antioxidant property is used to inhibit microbial and fungal growth to conserve food [10]. ...
Aims : This study aims to determine the organoleptic characteristics of different formulations nectars elaborated with ginger oleoresin. Study Design : Ginger nectars were formulated, using a composite central plan, from oleoresin or ginger rhizome, lemon juice and sugar. Then, they were subjected to sensory analyzes. Place and Duration of Study : The study was conducted, between November and December 2017, at the Biochemistry and Food Sciences Laboratory of the Félix Houphouët-boigny University. Methodology : Seventeen (17) nectars formulas were established by considering varying amounts of three ingredients: oleoresin (X1), sugar (X2) and lemon juice (X3) according to a composite experimental plan. The acceptance of these nectar formulas with consumers has been estimated. The intensities of perception of their color, texture and flavor were also evaluated relative to the artisanal nectar of ginger taken as a control. The sensory evaluation was carried out by panels of tasters. Results : The hedonic analysis indicates that in addition to the control Ft accepted at 91.43% by the tasters, the formulations F2; F8; F12; F13 and F14 are preferred in proportions ranging from 57.14% to 77.15%. The intensities of the organoleptic characteristics of these nectars are translated by sensory profiles. The formulations F2; F8; F12; F13 and F14 are yellow while the control is brown. As regards the texture, the control has a turbidity more pronounced than the formulations. While the intensities of the fluidity and homogeneity are higher for formulations F2; F8; F12; F13 and F14 than the control. In addition, the control Ft appears sweeter and more acidic than the formulations. This character is also observed in the flavors of gnamankou and lemon. Conclusion : The formulations F2; F8; F12; F13 and F14 close to the witness would be indicators for producers of ginger nectar.
Gastric cancer (GC), the third leading cause of cancer-related death globally, is complex and heterogeneous. This review explores multidisciplinary investigations of traditional Chinese medicine (TCM) combined with Western medical practices, emphasizing the development of nutraceuticals for cancer prevention. Using advanced analytical chemistry and food chemistry techniques, this study investigated how TCM components may be optimized for nutraceutical development. Focusing on molecular interactions with GC pathways, particularly the NF-κB, PI3K/Akt, and Wnt/β-catenin pathways, we examined the effects of TCM polyherbal formulas, extracts, and isolated compounds. These agents modulate apoptosis and cellular proliferation, underscoring their potential in preventive strategies. The convergence of nutraceutical and medicine food homology studies highlights a significant shift towards integrating TCM-derived compounds in a preventive health framework. This approach aims not only to enhance efficacy and reduce side effects but also to champion a preventive paradigm using personalized medicine to advance proactive health maintenance and disease prevention. The combination of TCM and western medical practices offers promising avenues for future research and practical applications in GC prevention.
https://authors.elsevier.com/a/1jsM1AUp3caCPN
Zingiber officinale Roscoe, widely known as ginger, holds significant importance both as a spice and a medicinal plant in traditional and folk medicines. Ginger oil, derived from its rhizomes, exhibits broad pharmacological effects and is often utilized in natural formulations to manage gastrointestinal and respiratory diseases effectively. The plant is rich in diverse chemical constituents, including phenolic compounds, terpenes, polysaccharides, lipids, organic acids, and raw fibers. The health-promoting properties of ginger are primarily attributed to its phenolic compounds such as gingerols and shogaols. Extensive research has highlighted ginger's manifold biological activities, encompassing antioxidant, anti-inflammatory, antimicrobial, anticancer, neuroprotective, cardiovascular protective, respiratory protective, anti-obesity, anti-diabetic, anti-nausea, and anti-emetic effects. This review consolidates current understanding of ginger's bioactive compounds and their diverse bioactivities.
To investigate the mechanism of action of Banxia-Shengjiang drug pair on the inhibition of gastric cancer (GC) using network pharmacology and bioinformatics techniques. The action targets of the Banxia ( Pinellia ternata (Thunb.) Makino ) -Shengjiang ( Zingiber officinale Roscoe ) drug pair obtained from the TCMSP database were intersected with differentially expressed genes (DEGs) and GC-related genes, and the intersected genes were analyzed for pathway enrichment to identify the signaling pathways and core target genes. Subsequently, the core target genes were analyzed for clinical relevance gene mutation analysis, methylation analysis, immune infiltration analysis and immune cell analysis. Finally, by constructing the PPI network of hub genes and corresponding active ingredients, the key active ingredients of the Banxia-Shengjiang drug pair were screened for molecular docking with the hub genes. In this study, a total of 557 target genes of Banxia-Shengjiang pairs, 7754 GC-related genes and 1799 DEGs in GC were screened. Five hub genes were screened, which were PTGS2, MMP9, PPARG, MMP2, and CXCR4. The pathway enrichment analyses showed that the intersecting genes were associated with RAS/MAPK signaling pathway. In addition, the clinical correlation analysis showed that hub genes were differentially expressed in GC and was closely associated with immune infiltration and immunotherapy. The results of single nucleotide variation (SNV) and copy number variation (CNV) indicated that mutations in the hub genes were associated with the survival of gastric cancer patients. Finally, the PPI network and molecular docking results showed that PTGS2 and MMP9 were potentially important targets for the inhibition of GC by Banxia-Shengjiang drug pair, while cavidine was an important active ingredient for the inhibition of GC by Banxia-Shengjiang drug pair. Banxia-Shengjiang drug pair may regulate the immune function and inhibit GC by modulating the expression of core target genes such as RAS/MAPK signaling pathway, PTGS2 and MMP9.
Since ancient times, ginger (Zingiber officinale Roscoe, Zingiberaceae) has been used in Chinese, Ayurvedic, and Tibb-Unani herbal medicines all over the world for a variety of unrelated illnesses. Rheumatism, arthritis, sprains, sore throats, cramps, constipation, indigestion, vomiting, fever, infectious diseases, and helminthiasis are a few of these conditions. Ginger is currently experiencing a resurgence in popularity, and a large number of scientific studies are being carried out to determine the active ingredients of the plant, validate its pharmacological actions and constituents, and provide evidence for the plant's application in treating a range of diseases. This article's objective is to review the most notable recent reports on these investigations. Ginger and the compounds extracted from it have a multitude of pharmacological properties, including anti-inflammatory, anti-tumorigenic, anti-apoptotic, anti-hyperglycaemic, anti-lipidemic, and anti-emetic effects. Strong antioxidants like ginger have the power to reduce or even stop the production of free radicals. It's believed to be a safe herbal remedy with very minor negative effects. Further studies on the kinetics of ginger and its components, as well as the long-term effects of consumption in humans and animals are required.
Gastric cancer (GC) is a serious global health concern. GC is a form of cancer that advances through the stomach lining. Therefore, there is a need to explore novel preventive strategies for GC. A novel study indicated that plant-derived compounds have significant anticancer characteristics and may provide a novel therapeutic approach for GC. Recent research has highlighted the potential role of natural compounds, particularly phytocompounds, in preventing GC. Compounds, such as curcumin, resveratrol, and epigallocatechin gallate, have significant anticancer properties against GC. The primary purpose of this study was to investigate the preventive properties of the phytocompounds against GC. The experimental findings included both in vitro and in vivo studies, clinical trials, and epidemiological investigations, providing a comprehensive evaluation of the potential impact of compounds on GC prevention. This review also provides a detailed overview of the probable medicinal effects of phytocompounds on the avoidance and treatment of GC, considering their complex molecular mechanisms of action, bioavailability, and safety. This study provides new perspectives on the possible significance of compounds in GC treatment and emphasizes their promise as a cutting-edge approach to anti-cancer methods.
Rapid and sustainable green technology was implemented in the current study to fabricate Ti nanoparticles. The vegetable ginger with the scientific name Zingiber officinale was employed as a biological source in the fabrication process of nanoparticles. The optical, structural, morphological, and particle size of the fabricated Ti nanoparticles were characterized with the help of UV-visible absorption spectrum, FTIR (Fourier Transform Infrared) spectrum, SEM (Scanning Electron Microscope) analysis, DLS (Dynamic Light Scattering) technique and XRD (X-ray powder diffraction) crystallography technique. The presence of spherical-shaped Ti nanoparticles with an average particle size of 93 nm was confirmed based on these characterization techniques. The anti-cancer properties of the Z. officinale mediated Ti nanoparticles were analyzed through MTT assay against cell lines MCF-7 (Human breast adenocarcinoma cell line) and concentration-dependent anti-cancer properties were observed. The anti-inflammatory capacity of the Z. officinale mediated Ti nanoparticles were examined through protein denaturation assay and nitric oxide scavenging assay. The antioxidant capacity of the Z. officinale mediated Ti nanoparticles were examined through DPPH assay, hydrogen peroxide radical scavenging assay, hydroxyl radical scavenging assay, and FRAP (Ferric Reducing Antioxidant Power) analysis. The fabricated Ti nanoparticles exhibited anti-inflammatory and antioxidant capacity in a concentration-dependent pattern.
When compared to chemical medicines, herbal medicines have the greatest therapeutic benefit while having fewer harmful side effects. Many different components in herbs have an anticancer impact, but the exact mechanism of how they work is unknown. Some herbal medicines have even been shown to trigger autophagy, a process that has shown promise as a potential cancer treatment. In the past ten years, autophagy has come to be recognised as a crucial mechanism in the maintenance of cellular homeostasis, which has led to the discovery of its implications in the pathology of the majority of cellular environments as well as human disorders. Autophagy is a catabolic process that is used by cells to maintain their homeostasis. This process involves the degradation of misfolded, damaged, and excessive proteins, as well as nonfunctional organelles, foreign pathogens, and other cellular components. Autophagy is a highly conserved process. In this review article, several naturally occurring chemicals are discussed. These compounds offer excellent prospects for autophagy inducers, which are substances that can hasten the death of cells when used as a complementary or alternative treatment for cancer. It requires additional exploration in preclinical and clinical investigations, notwithstanding recent advances in therapeutic medications or agents of natural products in numerous cancers. These advancements have been made despite the need for further investigation.
The prevention and treatment of skin diseases remains a major challenge in medicine. The search for natural active ingredients that can be used to prevent the development of the disease and complement treatment is on the rise. Natural extracts of ginger and hemp offer a wide range of bioactive compounds with potential health benefits. This study evaluates the effectiveness of hemp and ginger extract as a supportive treatment for skin diseases. It reports a synergistic effect of hemp and ginger extract. The contents of cannabinoids and components of ginger are determined, with the highest being CBD (587.17 ± 8.32 µg/g) and 6-gingerol (60.07 ± 0.40 µg/g). The minimum inhibitory concentration for Staphylococcus aureus (156.5 µg/mL), Escherichia coli (625.2 µg/mL) and Candida albicans (78.3 µg/mL) was also analyzed. Analysis of WM-266-4 cells revealed the greatest decrease in metabolic activity in cells exposed to the extract at a concentration of 1.00 µg/mL. Regarding the expression of genes associated with cellular processes, melanoma aggressiveness, resistance and cell survival, a significant difference was found in the expression of ABCB5, CAV1 and S100A9 compared with the control (cells not exposed to the extract).
Rhizomatous plants have been sources of remedy and were used widely as dietary spices and flavor. Their effects as immunomodulators are also documented. Several studies have confirmed that both Curcuma longa (turmeric) and Zingiber officinale (ginger) have a vast array of medicinal and immunomodulatory properties. Curcumin, which is one of the main curcuminoids of Curcuma longa, possesses various pharmacological properties, including immunomodulatory activities. Similarly, Zingiber officinale has a history of medicinal use for over 2500 years as one of the most versatile medicinal plants, which is traced to its bioactive compounds such as gingerol, paradol, shogaols, etc. The extracts and/or bioactive compounds from those plants are promising drug candidates against various diseases such as diabetes mellitus, bacterial infection, Alzheimer’s disease, rheumatoid arthritis, and cancer, partly via their immunomodulatory properties. Several studies have identified some of the bioactive compounds in Curcuma longa and Zingiber officinale rhizomes as potential inhibitors of the novel coronaviruses responsible for the COVID-19 pandemic. Such bioactive compounds are eligible for further investigation of the potential to treat COVID-19 patients effectively. This chapter describes the regulation of immune responses by rhizomatous Curcuma longa and Zingiber officinale for the treatment of diseases of diverse origin.KeywordsRhizomatous plantsImmunomodulator
Curcuma longa
CurcuminCoronavirus
Zingiber officinale
Gingerol
Gastric cancer (GC) is one of the most frequent cancers in the world, whereas is ranked as the 4th most prevalent cancer and the second important reason of cancer death. Regrettably, GC is often diagnosed at a progressive phase; whereas the majority of patients are not having qualification for the remedial therapies in this stage. In addition, existing systemic chemotherapy exhibit the low efficiency and minimum survival profits. Now, GC therapy is multidisciplinary, and multiple option strategies are well-known; therefore, the present study reviewed the new insight into chemotherapy agents and various alternative and complementary strategies such as neoadjuvant &Adjuvant therapy, nanotherapy, natural medicines, etc. which are suggested for GC treatment. Moreover, we reviewed the current surgery techniques such as endoscopic resection, laparoscopic resection. We also summarized new insights into pathophysiology, epidemiology, risk factors, diagnosis, prevention and screening approaches in the GC.
Zingiber officinale Roscoe is a well-recognized herbal plant throughout the world. Ginger is not only consumed as dietary spice but has also been employed in the traditional medicinal systems as herbal remedy since antiquity. Ginger offers health benefits mainly attributable to many bioactive phytochemicals including phenolic compounds, terpenes, flavonoids, carbohydrates, proteins, minerals, and many more. The principle phenolic compounds in ginger that lead to a plethora of biological activities are gingerols, shogaols, and paradols. Rhizome is an essential nutritional and medicinal component of ginger. The volatile components impart characteristic aroma or fragrance to ginger. This spice is traditionally used to relieve pain, constipation, digestive troubles, fever, cramps, inflammation, hypertension, dementia, and infections. Accumulated evidences have illustrated that ginger and its derivatives exhibit multiple pharmacological effects including antioxidant, anti-inflammatory, antidiabetic, antiemetic, anti-obesity, antimicrobial, anticancer, cardioprotective, and neuroprotective. Ginger thus can be used as potent and innovative therapeutic alternative for the prevention and management of acute and chronic disorders. This chapter highlights current knowledge about the ethanobotanical uses, phytochemicals, and biological activities of ginger and suggests that this updated information will be fruitful for researchers to investigate novel and unexplored applications.KeywordsAdrackGingerGingerolOleoresinParadolsPhenylpropanoidsSonth
Zingiber officinale
Zingiber zingiber
Background:
Modulation of non-specific immunity and other related activities of succulent parts of effective medicinal plants can prevent viral infections like COVID-19 through their dietary intake.
Objective:
The succulent parts of the medicinal plants with immunomodulation, anti-oxidation, anti-viral, anti-inflammatory, etc . power can be used orally in the capsular form to prevent as well as to reduce the severity of symptoms of COVID-19.
Methods:
A proposal is displayed with a detailed description of related steps like the selection of medicinal plant parts consulting related reports, collection of biomedicines, validation of efficacy, dosing, encapsulation, storage, and transportation, etc .
Results:
The succulent bio-medicines against COVID-19 can be developed and marketed following only some adoptive research.
Conclusion:
Succulent bio-medicines can be prepared and marketed for the prevention and cure of different infectious and non-infectious diseases.
Gastric cancer belongs to the heterogeneous malignancies and, according to the World Health Organization, it is the fifth most commonly diagnosed cancer in men. The aim of this review is to provide an overview on the role of natural products of plant origin in the therapy of gastric cancer and to present the potentially active metabolites which can be used in the natural therapeutical strategies as the support to the conventional treatment. Many of the naturally spread secondary metabolites have been proved to exhibit chemopreventive properties when tested on the cell lines or in vivo. This manuscript aims to discuss the pharmacological significance of both the total extracts and the single isolated metabolites in the stomach cancer prevention and to focus on their mechanisms of action. A wide variety of plant‐derived anticancer metabolites from different groups presented in the manuscript that include polyphenols, terpenes, alkaloids, or sulphur‐containing compounds, underlines the multidirectional nature of natural products.
Spices play a unique role in food preparation and provide ethnic identity to cuisines. Spices are appreciated not only for their flavor but also known for their healing effects on both chronic or lethal diseases such as diabetes and cancer. A large corpus of scientific studies supports the cancer-preventive properties of spices, such as garlic, ginger, chili pepper, turmeric, cloves, cinnamon, saffron, and cardamom, the most common flavoring food items used globally. The focus of this review is on these spices that contain multiple bioactive compounds, some of which, in experimental models and human clinical studies, have shown significant anticancer and cancer preventive activities. The presence of high amounts of bioactive compounds such as alkaloids, flavones, polyphenols, triterpenes, and saponins in common spices have the potential to function as medicines that can prevent chronic metabolic diseases and even cancer. As anti-oxidants, anti-inflammatory, immune function modulators, and inducers of apoptosis in tumor cells, the bioactive compounds may be useful as single agents or as adjuvants. The molecular mechanisms of their biological action are their abilities to induce epigenetic modifications such as methylation, acetylation, ubiquitination, and suppression of lipid peroxidation. The low toxicity of these spices makes them favorable as chemopreventive agents. However, the significant therapeutic efficacy of these compounds in scientific clinical trials is still equivocal. Rigorous studies on human subjects are required to improve their bioavailability and standardize their clinical effectiveness. Such studies could define appropriate intervention strategies for maximum benefits from the dietary spices.
Background: Gentamicin (GEN) is an aminoglycoside antibiotic that is widely used
in clinical practice in treatment of severe gram negative bacterial infections. Tomato lycopene
(LYC) and ginger are powerful antioxidants against free radicals and oxidative attacks. Aim
of the work: the aim of this study was to investigate the protective effects of tomato LYC and
Zingiber officinale ethyl acetate extract (ZOEAE) against GEN induced oxidative stress and
apoptosis on kidney of adult albino rats. Material and methods: the study was conducted for
10 days on 72 adult albino rats of both sexes, divided into six main groups; one control
(subdivided into 4 subgroups) and five treated groups (8 rats in each subgroup & group).
Apart from Group І (control groups) the treated groups are treated as follow: Group ІI (LYC)
treated orally with LYC (200 mg /kg/day). Group ІII (ZOEAE) treated orally with ZOEAE
(200 mg /kg/day). Group IV (GEN) treated with IP injection of GEN (67.4 mg/kg/day).
Group V (GEN + LYC) treated with GEN (67.4 mg/kg/day) along with LYC (200
mg/kg/day). Group VI (GEN + ZOEAE) treated with GEN (67.4 mg /kg/day) along with
LYC (200 mg/kg/day). All animals were sacrificed 24 hours after the last dose, their blood
and kidney tissues were subjected to biochemical analysis, while the remining kidney tissues
were stained for histopathological study. Results: GEN administration for 10 days
significantly increased serum urea and creatinine concomitant with marked renal
histopathological changes, suggesting nephtotoxicity. Also, it significantly increased renal
malondialdehyde and decreased renal reduced glutathione and catalase activity, suggesting
free radical formation. GEN also caused DNA fragmentation, suggesting apoptosis. Coadministration
with either tomato LYC or ZOEAE produced approximate comprehensive
improvements of all studied parameters with the superiority of ZOEAE as regard
histopathology. Recommendations: supplementation with antioxidants e.g. LYC and
ZOEAE are recommended in GEN treated patients to protect against nephrotoxicity.
Keywords: Gentamicin – Lycopene - Ginger- Nephtotoxicity - Apoptosis - Oxidative Stress -
DNA fragmentation assay - DNA laddering.
Colorectal cancer (CRC) has been linked to dietary consumption of benzo[a]pyrene (B[a]P). 6-Gingerol (6-G), a component of ginger has been reported to possess anti-inflammatory and antioxidant activities, but little is known regarding the mechanism of 6-G in CRC chemoprevention. We therefore investigated the effect of 6-G on B[a]P. and dextran sulphate sodium (DSS) induced CRC in mice. Mice in Group I and Group II received corn oil and 6-G orally at 2ml/kg and 100 mg/kg, respectively for 126 days. Group III were administered 125 mg/kg of B[a]P for 5 days followed by 3 cycles of 4% dextran sulphate sodium (DSS). Group IV received 6-G for 7 days followed by co-administration with 125 mg/kg of B[a]P. for 5 days and 3 cycles of 4% DSS. Tumor formation was reduced and expression of Ki-67, WNT3a, DVL-2 and β-catenin following 6-G exposure. Also, 6-G increases expression of APC, P53, TUNEL positive nuclei and subsequently decreased the expression of TNF-α, IL-1β, INOS, COX-2 and cyclin D1. 6-G inhibited angiogenesis by decreasing the concentration of VEGF, Angiopoietin-1, FGF and GDF-15 in the colon of B[a]P. and DSS exposed mice. Overall, 6-G attenuated B[a]P and DSS-induced CRC in mice via anti-inflammatory, anti-proliferative and apoptotic mechanisms.
The aim of this study was to investigate if the declared benefits associated with superfoods are related to a specific molecular composition. For this purpose, untargeted metabolomics and molecular networking were used to obtain an overview of all features, focusing on compounds with anti-inflammatory, antioxidant or antimicrobial properties.
565 plant-based food samples were analyzed using UHPLC-HRMS and advanced data analysis tools.
The molecular networking of the whole dataset allowed identification of a greater diversity of molecules, in particular, prenol lipids, isoflavonoids and isoquinolines in superfoods, when compared with non-superfood species belonging to the same botanical family. Furthermore, in silico tools were used to expand our chemical knowledge of compounds observed in superfood samples.
This review article provides an overview on the current state of research in the area of microtubule-stabilizing agents from natural sources, with a primary focus on the biochemistry, biology, and pharmacology associated with these compounds. A variety of natural products have been discovered over the last decade to inhibit human cancer cell proliferation through a taxol-like mechanism. These compounds represent a whole new range of structurally diverse lead structures for anticancer drug discovery.
Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer.
To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.
TNF and Fas ligand induce apoptosis in tumor cells; however, their severe toxicity toward normal tissues hampers their application to cancer therapy. Apo2 ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand may be nontoxic to normal cells. To investigate Apo2L's therapeutic potential, we generated in bacteria a potently active soluble version of the native human protein. Several normal cell types were resistant in vitro to apoptosis induction by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not cause detectable toxicity to tissues and organs examined. Apo2L exerted cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung, breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed tumor progression, and improved survival. Apo2L cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation. Thus, Apo2L may have potent anticancer activity without significant toxicity toward normal tissues.
Purpose:
Microtubules are important cytoskeletal components involved in many cellular events. Antimicrotubule agents including polymerizing agents (paclitaxel and docetaxel) and depolymerizing drugs (vincristine, vinorelbine, and estramustine phosphate) are widely used either alone or in combination with other anticancer drugs. These antimicrotubule agents are promoters of apoptosis in cancer cells. In this review, we discuss the role of bcl-2 family genes in the regulation of apoptosis, and summarize effects of microtubule targeting agents on apoptotic signal transduction pathways.
Conclusion:
Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.
S-Nitrosylation of protein thiols is one of the cellular regulatory mechanisms induced by NO. The cysteine protease papain
has a critical thiol residue (Cys25). It has been demonstrated that NO or NO donors such as sodium nitroprusside and N-nitrosoaniline derivatives can reversibly inhibit this enzyme by S–NO bond formation in its active site. In this study, a
different regulated mechanism of inactivation was reported using S-nitrosothiols as the NO donor. FiveS-nitroso compounds,S-nitroso-N-acetyl-dl-penicillamine,S-nitrosoglutathione, S-nitrosocaptopril, glucose-S-nitroso-N-acetyl-dl-penicillamine-2, and the S-nitroso tripeptide acetyl-Phe-Gly-S-nitrosopenicillamine, exhibited different inhibitory activities toward the enzyme in a time- and concentration-dependent
manner with second-order rate constants (k
i/K
I) ranging from 8.9 to 17.2 m
−
1s−
1. The inhibition of papain byS-nitrosothiol was rapidly reversed by dithiothreitol, but not by ascorbate, which could reverse the inhibition of papain by
NOBF4. Incubation of the enzyme with a fluorescentS-nitroso probe (S-nitroso-5-dimethylaminonaphthalene-1-sulfonyl) resulted in the appearance of fluorescence of the protein, indicating the
formation of a thiol adduct. Moreover, S-transnitrosylation in the incubation of S-nitroso inactivators with papain was excluded. These results suggest that inactivation of papain byS-nitrosothiols is due to a direct attack of the highly reactive thiolate (Cys25) in the enzyme active site on the sulfur of S-nitrosothiols to form a mixed disulfide between the inactivator and papain.
Natural killer (NK) cells and interferon (IFN)-gamma have been implicated in immune surveillance against tumor development. Here we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays a critical role in the NK cell-mediated and IFN-gamma-dependent tumor surveillance. Administration of neutralizing monoclonal antibody against TRAIL promoted tumor development in mice subcutaneously inoculated with a chemical carcinogen methylcholanthrene (MCA). This protective effect of TRAIL was at least partly mediated by NK cells and totally dependent on IFN-gamma. In the absence of TRAIL, NK cells, or IFN-gamma, TRAIL-sensitive sarcomas preferentially emerged in MCA-inoculated mice. Moreover, development of spontaneous tumors in p53(+/-) mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors.
Apo-2L/TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor superfamily and has recently been shown to induce apoptosis through engagement of the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). The transcription factor nuclear factor (NF)-κB regulates the expression of genes involved in cancer cell invasion, metastasis, and resistance to chemotherapy. In normal unstimulated cells, NF-κB is maintained in the cytoplasm with its inhibitor protein IκB, whereas in cancer cells, NF-κB is in the nucleus and constitutively activates target genes. To understand the function of NF-κB in TRAIL-induced apoptosis, we have analyzed the specific roles of NF-κB subunits. Overexpression of a transdominant-negative mutant of the inhibitory protein IκBα results in down-regulation of constitutively active NF-κB, induction of DR5, and tumor necrosis factor receptor (TNFR) 1-associated death domain expression and enhancement of TRAIL sensitivity. Overexpression of RelA or a transcriptional-deficient mutant of c-Rel inhibits TRAIL-induced apoptosis. Depletion of RelA in mouse embryonic fibroblasts increases cytokine-induced apoptosis, whereas depletion of c-Rel blocks this process. Overexpression of RelA subunit inhibits caspase-8 and DR4 and DR5 expression and enhances expression of c-IAP1 and c-IAP2 after TRAIL treatment. By comparison, overexpression of c-Rel enhances DR4, DR5, and Bcl-Xs and inhibits cIAP1, cIAP2, and survivin after TRAIL treatment. These results suggest that the RelA subunit acts as a survival factor by inhibiting expression of DR4/DR5 and caspase-8 and up-regulating cIAP1 and cIAP2. The dual function of NF-κB, as an inhibitor or activator of apoptosis, depends on the relative levels of RelA and c-Rel subunits. Thus, NF-κB activity may play an important role in tumor progression, and down-regulation of RelA or up-regulation of c-Rel represents a possible therapeutic target for the treatment of cancer.
Different approaches to developing an accurate model of the binding conformation of paclitaxel (Taxol, PTX) on beta-tubulin are discussed. Electron crystallography, molecular modeling, NMR and synthetic studies all point to the T-Taxol conformation as the bioactive form. The range of molecular designs represented by synthetic taxoids prepared to test the latter, with an emphasis on internally bridged analogs, is summarized. Key implications and conclusions derived from the retrospective are presented.
NF-kappaB transcription factors are retained in the cytoplasm in an inactive form until they are activated and rapidly imported into the nucleus. We identified importin alpha3 and importin alpha4 as the main importin alpha isoforms mediating TNF-alpha-stimulated NF-kappaB p50/p65 heterodimer translocation into the nucleus. Importin alpha3 and alpha4 are close relatives in the human importin alpha family. We show that importin alpha3 isoform also mediates nuclear import of NF-kappaB p50 homodimer in nonstimulated cells. Importin alpha3 is shown to directly bind to previously characterized nuclear localization signals (NLSs) of NF-kappaB p50 and p65 proteins. Importin alpha molecules are known to have armadillo repeats that constitute the N-terminal and C-terminal NLS binding sites. We demonstrate by site-directed mutagenesis that NF-kappaB p50 binds to the N-terminal and p65 to the C-terminal NLS binding site of importin alpha3. In vitro competition experiments and analysis of cellular NF-kappaB suggest that NF-kappaB binds to importin alpha only when it is free of IkappaBalpha. The present study demonstrates that the nuclear import of NF-kappaB is a highly regulated process mediated by a subset of importin alpha molecules.
[6]-Gingerol, a pungent ingredient of ginger (Zingiber officinale Roscoe, Zingiberaceae), has a wide array of pharmacologic effects. The present study was aimed at unraveling the molecular mechanisms underlying previously reported antitumor promoting effects of [6]-gingerol in mouse skin in vivo. One of the well-recognized molecular targets for chemoprevention is cyclooxygenase-2 (COX-2) that is abnormally upregulated in many premalignant and malignant tissues and cells. In our present study, topical application of [6]-gingerol inhibited COX-2 expression in mouse skin stimulated with a prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Since the transcription factor nuclear factor-kappaB (NF-kappaB) is known to regulate COX-2 induction, we attempted to determine the effect of [6]-gingerol on TPA-induced activation of NF-kappaB. Pretreatment with [6]-gingerol resulted in a decrease in both TPA-induced DNA binding and transcriptional activities of NF-kappaB through suppression of IkappaBalpha degradation and p65 nuclear translocation. Phosphorylation of both IkappaBalpha and p65 was substantially blocked by [6]-gingerol. In addition, [6]-gingerol inhibited TPA-stimulated interaction of phospho-p65-(Ser-536) with cAMP response element binding protein-binding protein, a transcriptional coactivator of NF-kappaB. Moreover, [6]-gingerol prevented TPA-induced phosphorylation and catalytic activity of p38 mitogen-activated protein (MAP) kinase that regulates COX-2 expression in mouse skin. The p38 MAP kinase inhibitor SB203580 attenuated NF-kappaB activation and subsequent COX-2 induction in TPA-treated mouse skin. Taken together, our data suggest that [6]-gingerol inhibits TPA-induced COX-2 expression in mouse skin in vivo by blocking the p38 MAP kinase-NF-kappaB signaling pathway.
Isotypes of vertebrate tubulin have variable amino acid sequences, which are clustered at their C-terminal ends. Isotypes bind colchicine at different on-rates and affinity constants. The kinetics of colchicine binding to purified (unfractionated) brain tubulin have been reported to be biphasic under pseudo-first-order conditions. Experiments with individual isotypes established that the presence of beta(III) in the purified tubulin is responsible for the biphasic kinetics. Because the isotypes mainly differ at the C termini, the colchicine-binding kinetics of unfractionated tubulin and the beta(III) isotype, cleaved at the C termini, have been tested under pseudo-first-order conditions. Removal of the C termini made no difference to the nature of the kinetics. Sequence alignment of different beta isotypes of tubulin showed that besides the C-terminal region, there are differences in the main body as well. To establish whether these differences lie at the colchicine-binding site or not, homology modeling of all beta-tubulin isotypes was done. We found that the isotypes differed from each other in the amino acids located near the A ring of colchicine at the colchicine-binding site on beta tubulin. While the beta(III) isotype has two hydrophilic residues (serine(242) and threonine(317)), both beta(II) and beta(IV) have two hydrophobic residues (leucine(242) and alanine(317)). beta(II) has isoleucine at position 318, while beta(III) and beta(IV) have valine at that position. Thus, these alterations in the nature of the amino acids surrounding the colchicine site could be responsible for the different colchicine-binding kinetics of the different isotypes of tubulin.
Cysteine plays structural roles in proteins and can also participate in electron transfer reactions, when some structural folds provide appropriated environments for stabilization of its sulfhydryl group in the anionic form, called thiolate (RS(-)). In contrast, sulfhydryl group of free cysteine has a relatively high pK(a) (8,5) and as a consequence is relatively inert for redox reaction in physiological conditions. Thiolate is considerable more powerful as nucleophilic agent than its protonated form, therefore, reactive cysteine are present mainly in its anionic form in proteins. In this review, we describe several processes in which reactive cysteine in proteins take part, showing a high degree of redox chemistry versatility.
A computer program that progressively evaluates the hydrophilicity and hydrophobicity of a protein along its amino acid sequence has been devised. For this purpose, a hydropathy scale has been composed wherein the hydrophilic and hydrophobic properties of each of the 20 amino acid side-chains is taken into consideration. The scale is based on an amalgam of experimental observations derived from the literature. The program uses a moving-segment approach that continuously determines the average hydropathy within a segment of predetermined length as it advances through the sequence. The consecutive scores are plotted from the amino to the carboxy terminus. At the same time, a midpoint line is printed that corresponds to the grand average of the hydropathy of the amino acid compositions found in most of the sequenced proteins. In the case of soluble, globular proteins there is a remarkable correspondence between the interior portions of their sequence and the regions appearing on the hydrophobic side of the midpoint line, as well as the exterior portions and the regions on the hydrophilic side. The correlation was demonstrated by comparisons between the plotted values and known structures determined by crystallography. In the case of membrane-bound proteins, the portions of their sequences that are located within the lipid bilayer are also clearly delineated by large uninterrupted areas on the hydrophobic side of the midpoint line. As such, the membrane-spanning segments of these proteins can be identified by this procedure. Although the method is not unique and embodies principles that have long been appreciated, its simplicity and its graphic nature make it a very useful tool for the evaluation of protein structures.
Quantitative structure-activity relationships (QSARs) provide a useful tool for defining a mathematical relationship between chemical structure and toxicity, and for applying such statistically derived models for predicting the toxicity of untested chemicals. Outlier chemicals can be encountered both in the derivation of QSAR models as well as in their application. Information regarding the relationship between molecular descriptors and molecular mechanism of toxicity can provide insight into the origin of outlier behavior as well as guidance regarding the predictive limitations of such models. Comparison of measured toxicity data for fish and rats with baseline QSAR prediction provides a means of identifying outliers and for categorizing more specific molecular mechanisms.
The sulfhydryl groups of tubulin are highly reactive entities. The reactivity of the sulfhydryl groups is sensitive to the presence of tubulin ligands, making these groups excellent probes for the interaction of tubulin with ligands. When tubulin is reacted with N,N'-ethylenebis-(iodoacetamide), two intrachain cross-links form in the beta subunit. Formation of one of these cross-links is completely blocked by colchicine, podophyllotoxin, and nocodazole; formation of the other is blocked completely by maytansine, phomopsin A and GTP and partly by Vinca alkaloids. Different ligands also differ in their effect on the rate of alkylation of tubulin with iodo[14C]acetamide, with vinblastine and phomopsin A being strong inhibitors and maytansine having very little effect. Oxidation of certain key sulfhydryl groups can inhibit microtubule assembly. One of these sulfhydryl groups appears to be cys239, but there are others not yet identified. Sulfhydryl-oxidizing agents also interfere with microtubule-mediated processes in vivo, raising the question of the existence of a physiological regulator of microtubule assembly. Potential physiological regulators have been examined to see if they can control microtubule assembly in vitro at their physiological concentrations. Of the ones that have been examined, thioredoxin and thioredoxin reductase are much better candidates for being physiological regulators than are either cystamine or glutathione.
4-Hydroxynonenal, which is one of the most important products of lipid peroxidation, alters microtubular organization and structure in 3T3 fibroblasts. Changes in cell shape and the disappearance of microtubules are observed by immunofluorescence after incubation with the aldehyde, and the colchicine binding activity of tubulin from 3T3 cells is modified. Moreover, the aldehyde determines a decrease in the ability of purified tubulin to polymerize and to bind colchicine. These effects may be related to the interaction of the aldehyde with functional -SH groups of tubulin which are necessary for protein integrity and functions. Indeed, the addition of cysteine protects against the damaging effects of the aldehyde.
In the early stages of apoptosis changes occur at the cell surface, which until now have remained difficult to recognize. One of these plasma membrane alterations is the translocation of phosphatidylserine (PS) from the inner side of the plasma membrane to the outer layer, by which PS becomes exposed at the external surface of the cell. Annexin V is a Ca2+ dependent phospholipid-binding protein with high affinity for PS. Hence this protein can be used as a sensitive probe for PS exposure upon the cell membrane. Translocation of PS to the external cell surface is not unique to apoptosis, but occurs also during cell necrosis. The difference between these two forms of cell death is that during the initial stages of apoptosis the cell membrane remains intact, while at the very moment that necrosis occurs the cell membrane looses its integrity and becomes leaky. Therefore the measurement of Annexin V binding to the cell surface as indicative for apoptosis has to be performed in conjunction with a dye exclusion test to establish integrity of the cell membrane.
The CD95 (Fas/APO-1) and tumor necrosis factor (TNF) receptor pathways share many similarities, including a common reliance on proteins containing 'death domains' for elements of the membrane-proximal signal relay. We have created mutant cell lines that are unable to activate NF-kappaB in response to TNF. One of the mutant lines lacks RIP, a 74 kDa Ser/Thr kinase originally identified by its ability to associate with Fas/APO-1 and induce cell death. Reconstitution of the line with RIP restores responsiveness to TNF. The RIP-deficient cell line is susceptible to apoptosis initiated by anti-CD95 antibodies. An analysis of cells reconstituted with mutant forms of RIP reveals similarities between the action of RIP and FADD/MORT-1, a Fas-associated death domain protein.
Tumor necrosis factor α (TNF-α) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the transcription
factor nuclear factor kappa B (NF-κB), which suppresses apoptosis by an unknown mechanism. The activation of NF-κB was found
to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins
c-IAP1 and c-IAP2 were identified as gene targets of NF-κB transcriptional activity. In cells in which NF-κB was inactive,
all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to
suppress etoposide-induced apoptosis. Thus, NF-κB activates a group of gene products that function cooperatively at the earliest
checkpoint to suppress TNF-α–mediated apoptosis and that function more distally to suppress genotoxic agent–mediated apoptosis.
The migration of tissue cells requires interplay between the microtubule and actin cytoskeletal systems. Recent reports suggest that interactions of microtubules with actin dynamics creates a polarization of microtubule assembly behavior in cells, such that microtubule growth occurs at the leading edge and microtubule shortening occurs at the cell body and rear. Microtubule growth and shortening may activate Rac1 and RhoA signaling, respectively, to control actin dynamics. Thus, an actin-dependent gradient in microtubule dynamic-instability parameters in cells may feed back through the activation of specific signalling pathways to perpetuate the polarized actin-assembly dynamics required for cell motility.
The 20 cysteine residues of tubulin are heterogeneously distributed throughout its three-dimensional structure. In the present work, we have used the reactivity of these cysteine residues with 5, 5'-dithiobis(2-nitrobenzoic acid) (DTNB) as a probe to detect the global conformational changes of tubulin under different experimental conditions. The 20 sulfhydryl groups can be classified into two categories: fast and slow reacting. Colchicine binding causes a dramatic decrease in the reactivity of the cysteine residues and causes complete protection of 1.4 cysteine residues. Similarly, other colchicine analogs that bind reversibly initially decrease the rate of reaction; but unlike colchicine they do not cause complete protection of any sulfhydryl groups. Interestingly, in all cases we find that all the slow reacting sulfhydryl groups are affected to the same extent, that is, have a single rate constant. Glycerol has a major inhibitory effect on all these slow reacting sulfhydryls, suggesting that the reaction of slow reacting cysteines takes place from an open state at equilibrium with the native. Ageing of tubulin at 37 degrees C leads to loss of self-assembly and colchicine binding activity. Using DTNB kinetics, we have shown that ageing leads to complete protection of some of the sulfhydryl groups and increased reaction rate for other slow reacting sulfhydryl groups. Ageing at 37 degrees C also causes aggregation of tubulin as indicated by HPLC analysis. The protection of some sulfhydryl groups may be a consequence of aggregation, whereas the increased rate of reaction of other slow reacting sulfhydryls may be a result of changes in global dynamics. CD spectra and acrylamide quenching support such a notion. Binding of 8-anilino-1-naphthalenesulfonate (ANS) and bis-ANS by tubulin cause complete protection of some cysteine residues as indicated by the DTNB reaction, but has little effect on the other slow reacting cysteines, suggesting local effects.
A new set of estradiol derivatives bearing various substituents at the 2-position were synthesized in order to further elucidate the structural parameters associated with the antitubulin activity and cytotoxicity of 2-substituted estradiols. The potencies of the new compounds as inhibitors of tubulin polymerization were determined, and the cytotoxicities of the analogues in human cancer cell cultures were investigated. The substituents introduced into the 2-position of estradiol included E-3'-hydroxy-1'-propenyl, 2'-hydroxyethoxy, 3-N,N-dimethylaminoethylideneamino, 2'-hydroxyethylineneamino, (beta-3,4,5-trimethoxyphenyl)ethenyl, phenylethynyl, ethynly, 1'-propynyl, and cyano. The substituents conferring the ability to inhibit tubulin polymerization included E-3'-hydroxy-1'-propenyl, 2'-hydroxyethoxy, ethynyl, and 1'-propynyl. The remaining compounds were all inactive as inhibitors of tubulin polymerization when tested at concentrations of up to 40 microM. All of the compounds were cytotoxic in a panel of 55 human cancer cell cultures, and in general, the most cytotoxic compounds were also the most potent as inhibitors of tubulin polymerization. 2-(1'-Propynyl)estradiol displayed significant anticancer activity in the in vivo hollow fiber animal model.
Microtubules are dynamic polymers that play crucial roles in a large number of cellular functions. Their pivotal role in mitosis makes them a target for the development of anticancer drugs. Microtubule-damaging agents suppress microtubule dynamics, leading to disruption of the mitotic spindle in dividing cells, cell cycle arrest at M phase, and late apoptosis. A better understanding of the processes coupling microtubule damage to the onset of apoptosis will reveal sites of potential intervention in cancer chemotherapy. Inhibition of microtubule dynamics induces persistent modification of biological processes (M arrest) and signaling pathways (mitotic spindle assembly checkpoint activation, Bcl-2 phosphorylation, c-Jun NH(2)-terminal kinase activation), which ultimately lead to apoptosis through the accumulation of signals that finally reach the threshold for the onset of apoptosis or through diminishing the threshold for engagement of cell death. Microtubules serve also as scaffolds for signaling molecules that regulate apoptosis, such as Bim and survivin, and their release from microtubules affect the activities of these apoptosis regulators. Thus, sustained modification of signaling routes and changes in the scaffolding properties of microtubules seem to constitute two major processes in the apoptotic response induced by microtubule-interfering agents.
A water-soluble (at pH 8) aromatic disulfide [5,5′-dithiobis(2-nitrobenzoic acid)] has been synthesized and shown to be useful for determination of sulfhydryl groups.Several applications have been made to show its usefulness for biological materials.A study of the reaction of this disulfide with blood has produced some evidence for the splitting of disulfide bonds by reduced heme.
Caspase activation is the 'point of no return' commitment to cell death. Synthesized as inactive zymogens, it is essential that the caspases remain inactive until the death signal is received. It is known for the downstream executioner caspases-3 and -7 that the activation event is proteolytic cleavage, and this had been assumed to apply to the initiator caspases as well. However, recent studies conducted on caspases-2, -8 and -9 have challenged this tenet of caspase activation. In this review we focus on the molecular details of caspase activation, with emphasis on recent work that provides a pleasing explanation for the differential requirements for the activation of executioner and initiator caspases.
The core effectors of apoptosis encompass proteolytic enzymes of the caspase family, which reside as latent precursors in most nucleated metazoan cells. A majority of studies on apoptosis are based on the assumption that caspase precursors are activated by cleavage, a common mechanism for most protease zymogen activations. Although this appears to be true for the executioner caspases, recent research points to a distinct activation mechanism for the initiator caspases that trigger the apoptotic pathways. This mechanism is proximity-induced dimerization without cleavage, and its elucidation has led to the revision of concepts of feedback regulation of apoptosis.
Herbal medicines are widely used in the United States, with approximately one quarter of adults reporting use of an herb to treat a medical illness within the past year. Herbs contain complicated mixtures of organic chemicals, the levels of which may vary substantially depending upon many factors related to the growth, production, and processing of the herbal product. While many manufacturers attempt to provide products with consistent levels of suspected active ingredients through a process known as standardization, this technique has uncertain effects on the safety and efficacy of the final product. Herbs are considered to be dietary supplements in the United States and therefore are subjected to a very limited form of regulation and oversight. Although herbs are often believed to be "natural" and therefore safe, many dangerous and lethal side effects have recently been reported, including direct toxic effects, allergic reactions, effects from contaminants, and interactions with drugs and other herbs. Of the ten most commonly used herbs in the United States, systematic reviews have concluded that only four are likely to be effective, and there is very limited evidence to evaluate the efficacy of the approximately 20,000 other available herbal products. Because herbs may contain potent bioactive substances and are often marketed to treat specific diseases, many have argued that they should be subject to more stringent regulation, similar to over-the-counter drugs. To improve the safety and consistency of herbs, additional research is needed to define the pharmacology, stability, and bioavailability of these products.
A series of new analogues of 2-methoxyestradiol (1) were synthesized to further elucidate the relationships between structure and activity. The compounds were designed to diminish the potential for metabolic deactivation at positions 2 and 17 and were analyzed as inhibitors of tubulin polymerization and for cytotoxicity. 17alpha-methyl-beta-estradiol (30), 2-propynyl-17alpha-methylestradiol (39), 2-ethoxy-17-(1'-methylene)estra-1,3,5(10)-triene-3-ol (50) and 2-ethoxy-17alpha-methylestradiol (51) showed similar or greater tubulin polymerization inhibition than 2-methoxyestradiol (1) and contained moieties that are expected to inhibit deactivating metabolic processes. All of the compounds tested were cytotoxic in the panel of 55 human cancer cell cultures, and generally, the derivatives that displayed the most activity against tubulin were also the most cytotoxic.
The inhibitor of apoptosis proteins (IAPs) are a family of antiapoptotic proteins that bind and inhibit caspases 3, 7, and/or 9, but not caspase 8. Growing evidence also indicates that IAPs also modulate cell division, cell cycle progression, and signal transduction pathways. As our basic understanding of IAPs has increased, the knowledge is being translated into clinically useful applications in the diagnosis and treatment of malignancy. For example, IAPs such as survivin are being investigated as diagnostic markers for the presence of occult malignancy. In addition, IAP overexpression is a poor prognostic marker in a variety of solid tumors and hematologic malignancies. Finally, IAPs are attractive therapeutic targets, and efforts are under way to develop antisense and chemical IAP inhibitors that may be useful for the treatment of a variety of malignancies. For all of these potential clinical applications, however, the challenge remains to incorporate these findings into actual clinical practice.
Nuclear transport of proteins and RNA occurs through the nuclear pore complex and is mediated by a superfamily of transport receptors known collectively as karyopherins. Karyopherins bind to their cargoes by recognition of specific nuclear localization signals or nuclear export signals. Transport through the nuclear pore complex is facilitated by transient interactions between the karyopherins and the nuclear pore complex. The interactions of karyopherins with their cargoes are regulated by the Ras-related GTPase Ran. Ran is assisted in this process by proteins that regulate its GTPase cycle and subcellular localization. In this review, we describe several of the major transport pathways that are conserved in higher and lower eukaryotes, with particular emphasis on the role of Ran. We highlight the latest advances in the structure and function of transport receptors and discuss recent examples of steroid hormone receptor import and regulation by signal transduction pathways. Understanding the molecular basis of nuclear transport may provide insight into human diseases by revealing how nucleocytoplasmic trafficking regulates protein activity.
All higher organisms consist of an ordered society of individual cells that must communicate to maintain and regulate their functions. This is achieved through a complex but highly regulated network of hormones, chemical mediators, chemokines and other cytokines, acting as ligands for intra or extra-cellular receptors. Ligands and receptors of the tumor necrosis factor (TNF) superfamilies are examples of signal transducers, whose integrated actions influence the development, homeostasis and adaptive responses of many cells and tissue types. Apo2L/TRAIL is one of several members of the tumour necrosis factor superfamily that induce apoptosis through the engagement of death receptors. Apo2L/TRAIL interacts with an unusually complex receptor system, which in humans comprises two death receptors and three decoy receptors. This molecule has received considerable attention recently because of the finding that many cancer cell types are sensitive to Apo2L/TRAIL-induced apoptosis, while most normal cells appear to be resistant to this action of Apo2L/TRAIL. In this review, we specifically emphasise on the actions of Apo2L/TRAIL with respect to its apoptotic signaling pathways and summarise what is known about its physiological role. The potential therapeutic usefulness of Apo2L/TRAIL, especially in combination with chemotherapeutic agents, is also discussed in some detail.
All 20 cysteine residues are accessible to disulphide reagents in the tubulin dimer, whereas only four are accessible in taxol-stabilized microtubules. Reaction rates with disulphide reagents are a function of the reagent, are decreased by G nucleotides, and increased with increase in pH and urea. With transient (stop-flow) kinetics, DTNB [5,5'-dithiobis-(2-nitrobenzoic acid)] and 2,2'-dithiodipyridine progress curves cannot be fitted by the sum of exponential terms based only on classes of cysteines. The mixed disulphide products react further to form both intra- and intermonomer disulphide bonds that can be reversed by reducing agents. With MMTS (methyl methanethiosulphonate) or ODNB (n-octyl-dithio-2-nitrobenzoate), virtually no protein-protein disulphide bonds are formed and the ODNB reaction can be given as the sum of three exponential terms with pseudo-first-order rate constants of 0.206, 0.069 and 0.010 s(-1) at pH 6.5, suggesting three classes of thiol reactivities. Limited cysteine substitution leads to only small changes in tryptophan or CD spectra, whereas complete substitution leads to loss of the helix content. MMTS-induced loss of SH groups leads to progressive increases in the critical concentration and loss of polymerization competence that can be reversed by assembly promoters such as higher protein concentration, taxol or high ionic strength. Under such conditions, the substituted tubulin forms protofilament-based structures such as microtubules, open tubules, sheets and/or bundles.
Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site.