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Upregulation of p53 Expression in Patients with Colorectal Cancer by Administration of Curcumin
Abstract
Biological therapies can be beneficial in cancer patients. The present study aims to examine the inhibitory mechanism of curcumin on cancer cells in patients with colorectal cancer. The results showed that curcumin administration increased body weight, decreased serum TNF-alpha levels, increased apoptotic tumor cells, enhanced expression of p53 molecule in tumor tissue, and modulated tumor cell apoptotic pathway. We conclude that the curcumin treatment improves the general health of patients with colorectal cancer via the mechanism of increased p53 molecule expression in tumor cells and consequently speeds up tumor cell apoptosis.
... Overall, these results showed that middle-aged, healthy people can benefit from lipidated curcumin [10]. Further studies have also highlighted the therapeutic benefits of curcumin, with the most important ones being improved circulation [11], metal chelation [12,13], treatment of cancer [11,14], playing the role of an anti-oxidant [9] and antiinflammatory agent [15,16], while also assisting neurogenesis [17]. Still more clinical trials have demonstrated the effectiveness of turmeric against diabetes, fibrosis, irritable bowel syndrome, acne, and lupus nephritis [18]. ...
... Curcumin, given in pill form at a dosage 360 mg thrice daily for a period of 10 to 30 days, demonstrated significant effects. The administration of curcumin through injections resulted in increased body weight and reduced levels of TNF-α in the bloodstream [15]. The reported study, like other studies presented above, prove how safe and efficient the said drug is for colorectal cancer patients, but also draw attention to the need for larger, randomized, and closely monitored clinical trials to validate its therapeutic benefits against colorectal cancer. ...
... (www.preprints.org) | NOT PEER-REVIEWED | Posted: 20 September 2024 doi:10.20944/preprints202409.1576.v115 ...
Treatment with herbal medicine continues to enjoy widespread popularity not only in the developing world, because of low costs, easy availability, and low risk of adverse effects. One such plant is Curcumin longa L., or turmeric, which has a long history of both culinary and medicinal uses throughout Asia, spanning thousands of years. In addition to traditionally being used as a dye, as a flavouring and colouring agent in foods, and, e.g., marriage rituals, turmeric is also notable for its long history of use to treat a variety of medical conditions, including inflammatory, bacterial, and fungal diseases and infections, jaundice, tumours, and ulcers among others. In light of this long history of use, it is not surprising to find that also modern biochemistry and clinical research studies show that a significant component of turmeric, curcumin, may have a multitude of therapeutic benefits, much of it attributed to the herb’s antioxidant qualities which are crucial for the prevention and treatment of, e.g., chronic inflammatory illnesses, conditions that often act as precursors for other serious diseases, including cancer and neurological disorders, such as Parkinsons and Alzheimer’s. Furthermore, investigations on the safety profile and toxicity of curcumin have shown that it is generally safe even at large dosages, although caution is necessary as curcumin also have documented anticoagulant effects. This article is focused on providing a better perspective into molecular mechanisms for possible actions along with an in-depth review of recent studies of curcumin, its beneficial role and therapeutic applications in chronic health conditions, with a focus on its cancer, inflammatory bowel disease, osteoarthritis, atherosclerosis, peptic ulcer, Covid19, psoriasis, vitiligo, and depression.
... Random sequence generation was identified in 16 trials and classified as having a low risk of bias in this domain [26,[30][31][32][33][34][35][36][38][39][40][41][42][43][44]46,50]. ...
... Sixteen studies reported data on allocation concealment [26,[30][31][32][33][34][35][36][38][39][40][41][42][43][44]50]. The blinding of participants and personnel was described in 15 studies [26,[30][31][32][33][34][35][36]38,[40][41][42][43][44]47,50], but the rest of studies did not apply any blinding method, or this was unclear. ...
... Sixteen studies reported data on allocation concealment [26,[30][31][32][33][34][35][36][38][39][40][41][42][43][44]50]. The blinding of participants and personnel was described in 15 studies [26,[30][31][32][33][34][35][36]38,[40][41][42][43][44]47,50], but the rest of studies did not apply any blinding method, or this was unclear. Outcome assessment blinding was thoroughly described in 14 studies [26,[30][31][32][33][34][35][36]38,[40][41][42][43][44]50]. ...
Polyphenols are plant metabolites with potential anti-inflammatory and anti-proliferative effects, which may be advantageous for disorders like colorectal cancer (CRC). Despite promising in vitro and in vivo evidence, human clinical trials have yielded mixed results. The present study aimed to evaluate the clinical evidence of polyphenols for CRC prevention or treatment. A systematic review was performed according to PRISMA. Based on a PROSPERO registered protocol (CRD42024560044), online databases (PubMed and COCHRANE) were utilized for the literature search. A total of 100 studies articles were initially identified. After reviewing, 12 studies with a low risk of bias were selected, examining the effect of a variety of compounds. Curcumin demonstrated promise in various trials, mainly decreasing inflammatory cytokines, though results varied, and it did not lower intestinal adenomas or improve outcomes after chemotherapy. Neither epigallocatechin gallate nor artepillin C reduced the incidence of adenomas. Finally, fisetin seemed to improve the inflammatory status of patients under chemotherapy (5-fluorouracil). In summary, although certain polyphenols appear to exert some effect, their role in the prevention or treatment of CRC is inconclusive, and more clinical studies under more controlled conditions are needed.
... In addition, supplementation with 360 milligrams three times daily increased the expression of the p53 protein, an essential protein in regulating the cell cycle and induction of programmed cell death (Z. He et al. 2011). This led to an increase in the amount of apoptosis that was induced in patients with colon cancer (Z. ...
... This led to an increase in the amount of apoptosis that was induced in patients with colon cancer (Z. He et al. 2011). In addition to this, it decreased TNF-α levels by enhancing the patients' overall inflammatory condition (Z. ...
... In addition to this, it decreased TNF-α levels by enhancing the patients' overall inflammatory condition (Z. He et al. 2011). ...
... A 40 mg/kg body weight (b.w) intravenous dose of curcumin given to rats resulted in complete plasma clearance at one hour post-dose. An oral dose of 500 mg/kg b.w given to rats resulted in a peak plasma concentration of only 1.8 mg/Ml (He et al., 2011;Tiwari et al., 2021). ...
... intake of 1.44 gram of curcumin for 6 to 36 months, resulted in suppression of prostrate specific antigen in 97 prostrate cancer patients (Choi et al., 2019). There was increased expression of P53 gene in 26 patients that were administered 1.08 gram of curcumin between 10 to 30 days in patients suffering from colorectal cancer (He et al., 2011). ...
Cancer is a leading cause of mortality that is characterized by uncontrolled cell proliferation above hay-flick limit (tumor growth), hypoxia in affected tissue and resulting to angiogenesis, apoptosis and metastasis. It adversely affects patients: psychologically, socially as well as economically. It results due to interplay of risk factors like; chemicals, viruses, genetic predisposition and environmental factors. There is global quest for safer, effective and cheaper strategies in cancer treatment which include use of phytochemicals obtained from plants. Turmeric has a very potent component, curcumin that has greatly contributed towards the effective treatment of cancer. Curcumin possesses some properties that inhibit cell proliferation and simultaneously induce apoptosis as well as provide positive results in management of oxidative stress and inflammation. It has been reported in animal cell line and clinical trial to be highly effective in cancer treatment due to its availability, bioactivity and no observable adverse effect. The use of curcumin in cancer treatment needs to be encouraged by promoting its use in preparation of regular cuisines and as adjuvants in cancer treatment.
... D. Guo et al., 2013;G. Song et al., 2005) and in CRC tissues (He et al., 2011), others have reported that curcumin downregulates p53 protein levels (Shehzad et al., 2013). Remarkably, Howells and colleagues observed the proapoptotic effects of curcumin in CRC cells with either wild-type or mutant p53, suggesting that the natural substance induces apoptosis through both p53-dependent and p53-independent pathways (Howells et al., 2007). ...
... Ultimately, a goal of every cancer treatment is to induce a senescence-related cell cycle arrest as well as controlled cell death in tumor cells and this is also the focus in rapidly proliferating CRC. A clinical examination (Table 3) demonstrated the anti-inflammatory and apoptosis-inducing regulatory ability of curcumin via downregulation of TNF-α levels in the blood serum and simultaneous induction of the p53 signaling pathway (He et al., 2011). ...
Colorectal cancer (CRC) development and progression, one of the most common cancers globally, is supported by specific mechanisms to escape cell death despite chemotherapy, including cellular autophagy. Autophagy is an evolutionarily highly conserved degradation pathway involved in a variety of cellular processes, such as the maintenance of cellular homeostasis and clearance of foreign bodies, and its imbalance is associated with many diseases. However, the role of autophagy in CRC progression remains controversial , as it has a dual function, affecting either cell death or survival, and is associated with cellular senescence in tumor therapy. Indeed, numerous data have been presented that autophagy in cancers serves as an alternative to cell apoptosis when the latter is ineffective or in apoptosis-resistant cells, which is why it is also referred to as programmed cell death type II. Curcumin, one of the active constituents of Curcuma longa, has great potential to combat CRC by influencing various cellular signaling pathways and epige-netic regulation in a safe and cost-effective approach. This review discusses the efficacy of curcumin against CRC in vitro and in vivo, particularly its modulation of autophagy and apoptosis in various cellular pathways. While clinical studies have assessed the potential of curcumin in cancer prevention and treatment, none have specifically examined its role in autophagy. Nonetheless, we offer an overview of potential correlations to support the use of this polyphenol as a prophylactic or co-therapeutic agent in CRC.
K E Y W O R D S apoptosis, autophagy, colorectal cancer, curcumin, senescence
... Furthermore, curcumin inhibited CRC growth by decreasing proinflammatory TNF-α and enhancing pro-apoptotic p53 [59]. At the molecular level, an interruption of the intercellular, tumor-and inflammation-promoting cross-talk between different components of the tumor microenvironment is particularly relevant, with fortunately modulatory support from secondary plant compounds such as resveratrol, curcumin, and calebin A [7,60,61]. ...
... The turmeric compounds curcumin and calebin A have shown strong anti-CRC effects preclinically [7,8]. While this was confirmed clinically for curcumin [59], calebin A has not been studied in this respect. In the following, we summarized the modes of action of both curcuminoids in CRC cells. ...
Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds. Calebin A and curcumin, two polyphenolic turmeric ingredients derived from the Asian Curcuma longa plant, demonstrate versatile anti-inflammatory and cancer-reducing abilities, including CRC-combating capacity. After an insight into their epigenetics-modifying holistic health-promoting effects, this review compares functional anti-CRC mechanisms of multi-targeting turmeric-derived compounds with mono-target classical chemotherapeutic agents. Furthermore, the reversal of resistance to chemotherapeutic drugs was presented by focusing on calebin A's and curcumin's capabilities to chemosensitize or re-sensitize CRC cells to 5-FU, oxaliplatin, cisplatin, and irinotecan. Both polyphenols enhance the receptiveness of CRC cells to standard cytostatic drugs converting them from chemoresistant into non-chemoresistant CRC cells by modulating inflammation, proliferation, cell cycle, cancer stem cells, and apoptotic signaling. Therefore, calebin A and curcumin can be tested for their ability to overcome cancer chemoresistance in preclinical and clinical trials. The future perspective of involving turmeric-ingredients curcumin or calebin A as an additive treatment to chemotherapy for patients with advanced metastasized CRC is explained.
... Curcumin demonstrates significant anticancer properties by modulating key molecular signaling pathways, leading to apoptosis and inhibiting tumor growth and metastasis [22]. It effectively suppresses NF-κB by inhibiting IkBs, thereby reducing the expression of pro-inflammatory genes, like TNF-α ( Figure 3) [23,24]. Additionally, curcumin downregulates AP-1, which is associated with anti-apoptotic proteins, promoting cancer cell death [25]. ...
Herbal medicine, particularly in developing regions, remains highly popular due to its cost-effectiveness, accessibility, and minimal risk of adverse effects. Curcuma longa L., commonly known as turmeric, exemplifies such herbal remedies with its extensive history of culinary and medicinal applications across Asia for thousands of years. Traditionally utilized as a dye, flavoring, and in cultural rituals, turmeric has also been employed to treat a spectrum of medical conditions, including inflammatory, bacterial, and fungal infections, jaundice, tumors, and ulcers. Building on this longstanding use, contemporary biochemical and clinical research has identified curcumin-the primary active compound in turmeric-as possessing significant therapeutic potential. This review hypothesizes that curcumin's antioxidant properties are pivotal in preventing and treating chronic inflammatory diseases, which are often precursors to more severe conditions, such as cancer, and neurological disorders, like Parkinson's and Alzheimer's disease. Additionally, while curcumin demonstrates a favorable safety profile, its anticoagulant effects warrant cautious application. This article synthesizes recent studies to elucidate the molecular mechanisms underlying curcumin's actions and evaluates its therapeutic efficacy in various human illnesses, including cancer, inflammatory bowel disease, osteoarthritis, atherosclerosis, peptic ulcers, COVID-19, psoriasis, vitiligo, and depression. By integrating diverse research findings, this review aims to provide a comprehensive perspective on curcumin's role in modern medicine and its potential as a multifaceted therapeutic agent.
... Research has found that administering curcumin to advanced colon cancer patients significantly reduces peripheral Treg cells while increasing Th1 cells [92]. Numerous clinical trials have proven the preventive and therapeutic effects of curcumin on colon cancer [93][94][95]. Ginsenoside Rg3, a steroidal saponin extracted from the ginseng, has been approved by the China Food and Drug Administration (CFDA) for the treatment of NSCLC. A study has shown that Rg3 can decrease chemotherapy-induced PD-L1 expression and restore T-cell cytotoxicity against cancer cells [96]. ...
More and more attention has been paid to the tumor microenvironment. The occurrence, development, metastasis, and drug resistance of tumor are closely related to the tumor microenvironment. At the same time, the application of traditional Chinese medicine (TCM) in tumor prevention and treatment has attracted more and more attention due to its regulatory effect on tumor cells and tumor microenvironment. The holistic view and multitarget regulatory view of TCM make it very suitable for the regulation of tumor microenvironment. This article will review the current research status of the molecular mechanism of TCM regulation of tumor microenvironment from three aspects: TCM can reverse the inhibitory phenotype of immune cells, TCM can enhance the immune response to tumor cells, and TCM clinical application.
... A substantial number of analyses of cancer cell lines suggest that Cur has an impact on a variety of molecular signaling pathways [2][3][4][5]. In addition, induction of apoptosis was observed in patient-related tissues after the treatment of tumor patients with Cur [6,7]. These results promoted the analysis of Cur in several clinical trials. ...
Curcumin (Cur) is a heavily used complementary derived drug from cancer patients. Spheroid samples derived from 82 patients were prepared and treated after 48 hours with two Cur formulations (CurA, CurB) in mono- and combination therapy. After 72 hours, cell viability and morphology were assessed. The Cur formulations had significant inhibitory effects of −8.47% (p < 0.001), CurA of −10.01% (−50.14–23.11%, p = 0.001) and CurB of −6.30% (−33.50–19.30%, p = 0.006), compared to their solvent controls Polyethylene-glycol, β-Cyclodextrin (CurA) and Kolliphor-ELP, Citrate (CurB). Cur formulations were more effective in prostate cancer (−19.54%) and less effective in gynecological non-breast cancers (0.30%). CurA showed better responses in samples of patients <40 (−13.81%) and >70 years of age (−17.74%). CurB had stronger effects in metastasized and heavily pretreated tumors. Combinations of Cur formulations and standard therapies were superior in 20/47 samples (42.55%) and inferior in 7/47 (14.89%). CurB stimulated chemo-doublets more strongly than monotherapies (−0.53% vs. −6.51%, p = 0.022) and more effectively than CurA (−6.51% vs. 3.33%, p = 0.005). Combinations of Cur formulations with Artesunate, Resveratrol and vitamin C were superior in 35/70 (50.00%) and inferior in 16/70 (22.86%) of samples. Cur formulations were significantly enhanced by combination with Artesunate (p = 0.020). Cur formulations showed a high variance in their anti-cancer effects, suggesting a need for individual testing before administration.
... Moreover, the presence of flavonoids, like quercetin, found mostly in Allium species, proved to have the ability to increase p53 expression, consequently speeding up tumor cell apoptosis in the experimental group. This is supported by the finding of the He et al. study, which concluded that the curcumin treatment improves the general health of patients with colorectal cancer via the mechanism of increased p53 molecule expression in tumor cells and consequently speeds up tumor cell apoptosis (He et al. 2011;Chan et al. 2013). ...
Gingival carcinoma is a malignant neoplasm affecting the oral mucosa and is
associated with significant morbidity and mortality. Allium ampeloprasum var.
porrum water extracts have gotten a lot of attention because of their bioactive
components, such as polyphenols, flavonoids, and alkaloids, which have a variety
of pharmacological activities, including antiproliferative actions. This study
aimed to evaluate the histological and molecular effects of Allium ampeloprasum
(leek) water extract on the proliferation of the murine gingival cancer cell
line. Histological evaluation was conducted to examine morphological changes
induced by extract treatment. Molecular mechanisms underlying the observed
histological changes were investigated using real-time polymerase chain
reaction (PCR). Expression levels of key genes associated with cell proliferation
and apoptosis were assessed. Histological findings revealed a dose-dependent
decrease (100, 50, 25, 12.5, and 6.25 μg/ml) in cell density and altered cell shape
in the treated cell line. Also, the percentage of inhibition for the oral mucosa cell
line was high, with a significant P of 0.006, in the treated group compared to the
control group. Additionally, water extract has an IC50 value of 61 g/ml. The P53
fold increment of gene expression is 0.6, which means the expression level in
the experimental condition is 60% higher than the control. This study provides
evidence for the potential antiproliferative activity of Allium ampeloprasum
water extract on the oral mucosa cell line. The observed histological changes,
coupled with the modulation of key genes involved in proliferation and apoptosis,
suggest that leek water extract may have therapeutic implications in managing
oral cancer
... A clinical study (phase II) on the anti-tumorigenic effects of curcumin on colorectal cancer revealed that administration of curcumin at 2 g and 4g in patients caused the prevention of colorectal neoplasia and decreased ACF levels 150. Further, the general health of patients with colorectal cancer was boosted by curcumin administration through enhanced expression of p53 molecule in tumour cells and consequent increase in cellular apoptosis 169 . ...
Curcumin is a biologically active phytochemical which manifests therapeutic activities in numerous health conditions, including cancer. Several curcuminoids obtained naturally and synthesized artificially also showcase anti-cancer and anti-tumorigenic effects. However, its water insolubility poses difficulties in its application to biological systems, lowering its availability in living tissues, which can be overcome by using various micro-encapsulation and nano-formulations of curcumin. When used in combination with other chemotherapeutic drugs, curcumin enhances the anti-carcinogen potential and reduces the side effects induced via chemotherapy. Structural modelling of basic pharmacophores of curcumin can enhance its biological and pharmacokinetic properties, as revealed by structure-activity relationship studies of curcumin. Various clinical trials of curcumin have proven its worth as an anti-neoplastic agent in humans, with minimal side effects. Its mechanism of action involves blockage of cell-signalling pathways and cellular enzymes, promotion of immunomodulatory effects and induction of programmed cell death in cancerous cells. Curcumin is an interesting molecule with diverse effects on various diseases, but its absolute potential has yet to be reached. Hence, more in-depth studies and clinical trials are needed. This review outlines curcumin’s chemical properties and summarizes its anti-cancer and pharmacokinetic potential.
... [45] The previous study demonstrated that curcumin of CL might induce apoptosis of cancer cells through upregulating p53 and activating caspase-3 in a dose-dependent manner. [46] In this study, the highest caspase-3 activity was reported from the administration of 60 µg/mL dose of CL alone, but in the other side, the lowest p53 expression was observed. Interestingly, the combination of 60 µg/mL CL and 31.25 mg/mL PN increase both caspase-3 activity and p53 expression. ...
... ERK and NF-κB expression [189]. Curcumin has been demonstrated to improve the overall health of people with colorectal cancer by promoting the p53 expression in tumor cells [190]. In Patients with familial adenomatous polyposis, it was found that curcumin decreases the size and number of the polyps with no substantial toxicity [191]. ...
... This molecular mechanism helps maintain redox homeostasis and enhance antioxidant capacity. Colorectal cancer 1.08 g/day 10-30 days ↓ TNF-α ↑ p53 expression and improve BMI [11] Rheumatoid arthritis 1.2 g/day 2 weeks Improvement in joint swelling, morning stiffness [12] Fatty liver disease 1 g/day 8 weeks ↓ BMI ↑ Liver function [13] The human gut microbiota is considered one of the densest and most active ecosystems of microorganisms and has a crucial function in maintaining human health. It consists of over one billion microorganisms, including bacteria, fungi, viruses, and protozoa [14]. ...
Curcumin (CUR) is a lipophilic natural polyphenol that can be isolated from the rhizome of turmeric. Studies have proposed that CUR possesses a variety of biological activities. Due to its anti-inflammatory and antioxidant properties, CUR shows promise in the treatment of inflammatory bowel disease, while its anti-obesity effects make it a potential therapeutic agent in the management of obesity. In addition, curcumin’s ability to prevent atherosclerosis and its cardiovascular benefits further expand its potential application in the treatment of cardiovascular disease. Nevertheless, owing to the limited bioavailability of CUR, it is difficult to validate its specific mechanism of action in the treatment of diseases. However, the restricted bioavailability of CUR makes it challenging to confirm its precise mode of action in disease treatment. Recent research indicates that the oral intake of curcumin may lead to elevated levels of residual curcumin in the gastrointestinal system, hinting at curcumin’s potential to directly influence gut microbiota. Furthermore, the ecological dysregulation of the gut microbiota has been shown to be critical in the pathogenesis of human diseases. This review summarizes the impact of gut dysbiosis on host health and the various ways in which curcumin modulates dysbiosis and ameliorates various diseases caused by it through the administration of curcumin.
... There are findings indicating that curcumin, applied in a dose of 360 mg three times a day for 30 days, can improve the health status of colorectal patients' cancer using the mechanism of increased expression of p53 in tumor cells [24]. Prostate cancer is the most common malignant disease affecting men which are usually controlled through prostate-specific antigen (PSA). ...
Cancer therapy is the most complex form of therapy, which in clinical practice involves the use of different classes of drugs with insufficient efficiency and pronounced side effects. Therefore, in recent years, the application and effectiveness of a large number of natural compounds on the therapeutic outcome and indications for various types of cancer therapy have been continuously investigated. Curcumin or diferuloylmethane is a bioactive, polyphenolic substance obtained by extraction from the rhizome of the plant Curcuma longa L., Zingiberaceae. It has a wide range of pharmacological activity through different molecular mechanisms and due to proven anti-inflammatory and anti-proliferative activity, special interest is directed toward the use of curcumin in oncology therapy. The aim of this paper is to summarize and critically analyze the collected data on the potential use of curcumin in cancer therapy. Curcumin modulates vital cellular responses such as cell cycle arrest, apoptosis, and cell differentiation, resulting in the activation of cascading molecular processes. Recent studies have shown the ability of curcumin to reduce the proliferation of cancer cells by inducing apoptosis, inhibiting angiogenesis, and reducing the expression of anti-apoptotic proteins. Also, studies in which curcumin was used as an adjuvant in oncology therapy resulted in a reduction in the side effects of therapy caused by the anticancer drugs. It has been proven that the combined use of curcumin with bevacizumab significantly reduces the growth of cancer cells without any recorded side effects. Current findings indicate the great potential of curcumin in the prevention and treatment of cancer and the use of curcumin as a therapeutic supplement in addition to conventional cancer immunotherapy.
... When curcumin is administered systemically, it quickly breaks down into metabolites including tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin, which are thought to have less biological activity than curcumin. The most common forms of curcumin found in blood are curcumin glucuronide, curcumin sulphate, and methylation curcumins [28,[48][49][50][51][52][53][54][55][56][57][58][59][60] . These conjugates have a reduced biological activity and are swiftly eliminated through urine and feces. ...
One of the primary concerns for women in good health is breast cancer. The most typical hazardous growth is this one. It spreads easily, and the clinical conditions are terrible. Bosom illness is the second‐most common type of malignant tumor that regularly causes women to pass away in the U.S. bosom malignant growth is the most well‐known disease among women worldwide, with 2.1 million cases reported in 2018 and more than 620,000 fatalities per year. Natural components are viewed as promising alternatives for the development of novel anti‐tumor drugs. Curcumin, also termed diferuloylmethane, is a yellow pigment made by the turmeric plant, Curcuma longa Linn. It is the curcuminoid and polyphenol present in the plant’s root that is most abundant. The antioxidant and anti‐inflammatory qualities of curcumin have been demonstrated, and it is frequently utilized in traditional medicine and cuisine. Due to its sophisticated pharmacological capabilities of chemoprevention and anticancer effects, curcumin, the main component of turmeric, has been linked to the treatment of breast cancer. The morbidity or mortality of the disease have not been significantly decreased by current breast cancer treatment options such as surgery, radiation, adjuvant chemotherapy, or hormone therapy. The expansion, estrogen receptor (trauma center), and human epidermal development factor receptor 2 (HER2) pathways are all involved in the activity of curcumin in illness. In breast cancer cells, curcumin is also known to regulate microRNA, cell stage-related characteristics, and apoptosis. This study reviews recent research on the atomic targets and anticancer effects of curcumin in breast cancer.
... In the curcumin treatment group, the impression of Bcl-2 was lowered while the impression of cleaved caspase-nine, and Bax cleaved caspase-three was increased. Moreover, we also Turmeric extract, oral intake; 3.6, 1.8 and 0.45 g per day Garcea et al. (2005) Colorectal 30 days 360 mg curcumin, 3 times per day, oral intake Increased tumour apoptotic cells numbers, increased p53 and Bax expression levels; reduced serum TNF-α levels, inhibition of Bls-2 expression He et al. (2011) examined the effect of curcumin on cell migration and cell aggressive ability. Curcumin lowered cell migration level (p < 0.05). ...
Cancer is the second leading cause of death in the world and one of the major public health problems. Curcumin has anticancer activity including inducing apoptosis and inhibiting proliferation and invasion of tumours by suppressing a variety of cellular signalling pathways. It also possesses anti-tumour activity on different human cancers such as breast cancer, lung cancer, head and neck squamous cell carcinoma, prostate cancer, and brain tumours. In vitro and in vivo trails, curcumin inhibits tumour development and metastasis by inhibiting many pathways that regulate signalling in malignant cells, including Ras, p53, extracellular signal-regulated kinases (ERK), Wnt-protein kinase B (Akt), MAPKs, and PI3K. Curcumin can also inhibit IKK, EGFR, -catenin, cyclin D1, tumour necrosis factor (TNF), and anti-apoptotic genes such as Bcl-X and Bcl-2 along with downregulating nuclear transcription factors like NF-κB, which reduces the formation of pro-inflammatory cytokines like chemokines, TNF-, Interleukins and IL-1, IL-2, IL-6, IL-8, IL-12.
Abbreviations: AP-1, activated protein 1; Bax, BCL-2-associated X protein; Bcl-XL, B-cell leukaemia extralarge; Cdc, cell division cycle; COX, cyclooxygenase; CY, cytochrome; DPPC, dipalmitoylphosphatidylcholine; EGFR, epidermal growth factor receptor; eIF, eukaryotic initiation factors; FOX, Forkhead box; FPTase, farnesyl protein transferase; HIF, hypoxia-inducible factor; histone deacetylase inhibitors, HLJ, DnaJ-like heat shock protein; Hsp, heat shock proteins; IL, interleukin; miRNA, micro ribonucleic acid; MMC, mitomycin-C; mTOR, mammalian target of rapamycin; NF-κB, nuclear transcription factor-kappa–B; PG, prostaglandins; PKB, protein kinase B; Ras, reticular activating system; TargOncol, human small cell lung cancer cell lines; TGF, transforming growth factor; TNF, tumour necrosis factor; TP, thymidine phosphorylase; TPA3, 12-O-tetradecanoylphorbol-13-acetate; u-PA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factors; XIAP, Xlinked inhibitor of apoptosis
... It has also been suggested to induce apoptosis by regulating several transcription factors, like p53, Erg-1, AP-1, β-catenin, Hif-1, Notch-1, and PPAR-α causing the down-regulation of Akt, EGFR, cMET cyclin D1, in CL-5 xenograft tumors (Lee et al. 2011). Recent findings from a number of studies suggest that CUR may be able to prevent metastasis by regulating multiple signaling pathways in a manner for which the underlying mechanisms are as of yet unclear (Zong et al. He et al. (2011) 2012). The NF-B signaling pathway has also been shown to be a crucial CUR-regulated mechanism (Zong et al. 2012). ...
Encapsulating curcumin (CUR) in nanocarriers such as liposomes, polymeric micelles, silica nanoparticles, protein-based nanocarriers, solid lipid nanoparticles, and nanocrystals could be efficient for a variety of industrial and biomedical applications. Nanofibers containing CUR represent a stable polymer-drug carrier with excellent surface-to-volume ratios for loading and cell interactions, tailored porosity for controlled CUR release, and diverse properties that fit the requirements for numerous applications. Despite the mentioned benefits, electrospinning is not capable of producing fibers from multiple polymers and biopolymers, and the product's effectiveness might be affected by various machine- and material-dependent parameters like the voltage and the flow rate of the electrospinning process. This review delves into the current and innovative recent research on nanofibers containing CUR and their various applications.
... There has been a growing interest in using traditional herbal medicines to create new drugs in recent years (Boroushaki et al., 2015;Dehnamaki et al., 2019;Zamanian et al., 2021). Research suggests that regular consumption of natural products can enhance patient well-being (He et al., 2011;Patel et al., 2010;Shokrzadeh et al., 2018). ...
Colon cancer (CC) is one of the most common and deadly cancers worldwide. Oncologists are facing challenges such as development of drug resistance and lack of suitable drug options for CC treatment. Flavonoids are a group of natural compounds found in fruits, vegetables, and other plant‐based foods. According to research, they have a potential role in the prevention and treatment of cancer. Apigenin is a flavonoid that is present in many fruits and vegetables. It has been used as a natural antioxidant for a long time and has been considered due to its anticancer effects and low toxicity. The results of this review study show that apigenin has potential anticancer effects on CC cells through various mechanisms. In this comprehensive review, we present the cellular targets and signaling pathways of apigenin indicated to date in in vivo and in vitro CC models. Among the most important modulated pathways, Wnt/β‐catenin, PI3K/AKT/mTOR, MAPK/ERK, JNK, STAT3, Bcl‐xL and Mcl‐1, PKM2, and NF‐kB have been described. Furthermore, apigenin suppresses the cell cycle in G2/M phase in CC cells. In CC cells, apigenin‐induced apoptosis is increased by inhibiting the formation of autophagy. According to the results of this study, apigenin appears to have the potential to be a promising agent for CC therapy, but more research is required in the field of pharmacology and pharmacokinetics to establish the apigenin effects and its dosage for clinical studies.
... According to the results, curcumin could decrease the levels of TNF-alpha in serum, which intuitively improve the conditions of patients. As a result, curcumin could not only promote cell apoptosis, but also enhance the level of p53 molecules in colorectal tissues [31]. In familial adenomatous polyposis (FAP), which would eventually develop into colorectal cancer, both the conventional managements with non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 showed severe adverse effects. ...
In the US, colon cancer has the third most mortality. Though new managements have reported upgraded prognosis, the five-year survival rates of patients with general or metastatic colon cancer are still unsatisfied at 64.7% and 20%, respectively. As a result, more innovative therapies or drugs with high efficacy should be developed. Curcumin, a natural chemical compound, is now in the spotlight of both preclinical and clinical trials on colon cancer. It not only exerts exceptional anti-cancer effects, but also anti-inflammatory and antiviral bio-activities. However, curcumin shows low bioavailability when orally administered. To resolve this issue, nanoparticles have been widely utilized. In this review, we precisely summarize the effects of curcumin on colon cancer in both preclinical and clinical studies. In vitro studies, curcumin could arrest cell cycle at the G2/M phase as well as part of the G1 phase, and induce cell apoptosis by binding to targeted molecules. Except for this, epigenetic alterations could also induce colon cancer. Both in vitro and in vivo studies have proved that curcumin could remarkably influence the prognosis. Moreover, genetically designed murine models which were orally administered with curcumin demonstrated satisfactory effects on colon cancer induced by different factors. More importantly, curcumin alone or as an adjuvant showed satisfactory results in numerous clinical trials. In conclusion, curcumin demonstrated outstanding anti-cancer activity against colon cancer.
... In addition, CUR treatment inactivated the PI3K pathway (Fu et al., 2018). In addition, the capsule form of CUR administration (360 mg) in CRC patients decreased TNF-α levels in serum, increased their body weight, augmented apoptosis of tumor cells, and upregulated p53 in tumor tissue (He et al., 2011). ...
Liver cancer is the sixth most prevalent cancer and ranks third in cancer-related death, after lung and colorectal cancer. Various natural products have been discovered as alternatives to conventional cancer therapy strategies, including radiotherapy, chemotherapy, and surgery. Curcumin (CUR) with antiinflammatory, antioxidant, and antitumor activities has been associated with therapeutic benefits against various cancers. It can regulate multiple signaling pathways, such as PI3K/Akt, Wnt/β-cate-nin, JAK/STAT, p53, MAPKs, and NF-ĸB, which are involved in cancer cell proliferation , metastasis, apoptosis, angiogenesis, and autophagy. Due to its rapid metabolism, poor oral bioavailability, and low solubility in water, CUR application in clinical practices is restricted. To overcome these limitations, nanotechnology-based delivery systems have been applied to use CUR nanoformulations with added benefits, such as reducing toxicity, improving cellular uptake, and targeting tumor sites. Besides the anticancer activities of CUR in combating various cancers, especially liver cancer, here we focused on the CUR nanoformulations, such as micelles, liposomes, polymeric, metal, and solid lipid nanoparticles, and others, in the treatment of liver cancer.
... Curcumin was also reported to induce p53 and Bax expression in patients with colorectal cancer, causing apoptosis and DNA fragmentation and suppressing TNF-α and Bcl-2. The treatment also improved patients' general health at a dosage of 360 mg thrice daily 262 . The combination of curcumin, 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in colorectal liver metastases reduced stem cell markers, such as aldehyde dehydrogenase and CD133 263 . ...
Turmeric (Curcuma longa) has been used for thousands of years for the prevention and treatment of various chronic diseases. Curcumin is just one of >200 ingredients in turmeric. Almost 7000 scientific papers on turmeric and almost 20,000 on curcumin have been published in PubMed. Scientific reports based on cell culture or animal studies are often not reproducible in humans. Therefore, human clinical trials are the best indicators for the prevention and treatment of a disease using a given agent/drug. Herein, we conducted an extensive literature survey on PubMed and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The keywords "turmeric and clinical trials" and "curcumin and clinical trials" were considered for data mining. A total of 148 references were found to be relevant for the key term "turmeric and clinical trials", of which 70 were common in both PubMed and Scopus, 44 were unique to PubMed, and 34 were unique to Scopus. Similarly, for the search term "curcumin and clinical trials", 440 references were found to be relevant, of which 70 were unique to PubMed, 110 were unique to Scopus, and 260 were common to both databases. These studies show that the golden spice has enormous health and medicinal benefits for humans. This Review will extract and summarize the lessons learned about turmeric and curcumin in the prevention and treatment of chronic diseases based on clinical trials.
... After treatment with curcumin, the samples from cancer patients depict increased body weight, lower TNF-alpha, enhanced apoptotic tumour cells and increased levels of p53 in tumour tissue (Ref. 157). The study report concluded that curcumin administration improves the cancer patient's health profile by altering the expression of p53 molecule. ...
The human oral cavity is comprised of dynamic and polynomial microbes which uniquely reside in the microenvironments of oral cavities. The cumulative functions of the symbiotic microbial communities maintain normal homeostasis; however, a shifted microbiota yields a dysbiosis state, which produces local and systemic diseases including dental caries, periodontitis, cancer, obesity and diabetes. Recent research reports claim that an association occurs between oral dysbiosis and the progression of different types of cancers including oral, gastric and pancreatic ones. Different mechanisms are proposed for the development of cancer, such as induction of inflammatory reactions, production of carcinogenic materials and alteration of the immune system. Medications are available to treat these associated diseases; however, the current strategies may further worsen the disease by unwanted side effects. Natural-derived polyphenol molecules significantly inhibit a wide range of systemic diseases with fewer side effects. In this review, we have displayed the functions of the oral microbes and we have extended the report regarding the role of polyphenols in oral microbiota to maintain healthy conditions and prevention of diseases with emphasis on the treatment of oral microbiota-associated cancer.
... In another study, subjects were given curcumin capsules at three different doses (3.6, 1.8, and 0.45 g/day) for 7 days and found that curcumin supplementation reduced the prostaglandin E2 levels [101]. Curcumin/standardized turmeric extract supplementation also reduced the M 1 G levels [102], aberrant crypt foci [103], improved body weight, reduced serum inflammatory biomarkers, and induced p53 protein expression [104]. The supplementation of curcuminoid is also found to be effective in pancreatic cancer by reducing the lipid peroxidation [105], mild anticancer activities [106], etc. Supplementation of turmeric extracts standardized to curcuminoids is also found to be effective in controlling the symptoms and biomarkers associated with pancreatic cancer. ...
Natural phytochemicals derived from plant extracts are used for a wide variety of applications, and research interest is going on a high pace utilizing the efficacy of various bioactive components. Consumer consciousness has led the scientists to deliver value-added products with the incorporation of various plant extracts. Turmeric, the “golden spice” is known from the Vedic cultures where it was used for regular homemade uses and for treating various disorders. It is one of the herbs which finds use from kitchen to clinical studies. Curcuminoids find their application to deliver health benefits, even in different forms. Innovative nutraceutical companies have focused on developing novel technologies to deliver value-added products. The chapter tries to present an overview on the various applications of curcuminoids in functional foods, nutraceuticals, molecular targets, and innovative technologies.
... A clinical randomized study assessed the anticancer effect of curcumin on CRC cells in 126 patients (He et al., 2011). Half of the patients received oral curcumin capsules at a dose of 360 mg/ Frontiers in Pharmacology frontiersin.org ...
Esophageal cancer (EC) is a common tumor of the gastrointestinal system and a major threat to human health. The etiology and incidence of EC vary depending on the type of pathology. Owing to the unique physiological structure of the esophagus and the poor biological behavior of EC, the treatment modalities available are limited, and the prognosis of patients is relatively poor. Curcumin is a type of natural phytochemical belonging to the class of phenolic compounds. It exerts favorable anticancer effects on various cancers. A growing body of evidence indicates that curcumin suppresses tumor development and progression by inhibiting tumor cell proliferation, invasion, and migration, thus inducing apoptosis, regulating microRNA expression, reversing multidrug resistance, and inducing sensitivity to the therapeutic effect of chemoradiotherapy. Multiple cellular molecules, growth factors, and genes encoding proteins participating in different signaling pathways interact with each other to contribute to the complex and orderly anticancer effect. The efficacy and safety of curcumin have been established in preclinical studies for EC and clinical trials for other cancers. However, the low bioavailability of curcumin limits its clinical application. Therefore, the modification of curcumin analogs, the combination of curcumin with other drugs or therapies, and the use of novel nanocarriers have been widely investigated to improve the clinical effects of curcumin in EC.
... This treatment significantly reduced the number and size of ileal and rectal adenomas, compared with the baseline (60.4% and 50.9%, respectively), without toxicity. Other studies demonstrated that a daily dose of curcumin (3.6 g in capsule form) improves the general health of colorectal cancer patients by increasing p53 molecule expression in tumor cells, and consequently, inducing tumor cell apoptosis [86,120]. ...
Given the stochastic complexity of cancer diseases, the development of chemotherapeutic drugs is almost limited by problems of selectivity and side effects. Furthermore, an increasing number of protective approaches have been recently considered as the main way to limit these pathologies. Natural bioactive compounds, and particularly dietary phenolic compounds, showed major protective and therapeutic effects against different types of human cancers. Indeed, phenolic substances have functional groups that allow them to exert several anti-cancer mechanisms, such as the induction of apoptosis, autophagy, cell cycle arrest at different stages, and the inhibition of telomerase. In addition, in vivo studies show that these phenolic compounds also have anti-angiogenic effects via the inhibition of invasion and angiogenesis. Moreover, clinical studies have already highlighted certain phenolic compounds producing clinical effects alone, or in combination with drugs used in chemotherapy. In the present work, we present a major advance in research concerning the mechanisms of action of the different phenolic compounds that are contained in food medicinal plants, as well as evidence from the clinical trials that focus on them.
... It has been reported that curcumin can induce apoptosis in human colon cancer HT29 cells [64]. In chemo-resistant CRC cells, curcumin can enhance the therapeutic potential of conventional chemotherapeutic drugs by inhibiting proliferative targets, including cyclin D1, NF-κB, phosphoinositide 3-kinase and Src [65]. Resveratrol, a natural stilbene found in wine and grapes, has been reported to inhibit signaling pathways involved in [66]. ...
Colorectal cancer (CRC) is a disease with high prevalence and mortality. Estimated preventability for CRC is approximately 50%, indicating that altering modifiable factors, including diet and body weight, can reduce CRC risk. There is strong evidence that dietary factors including whole grains, high-fiber, red and processed meat, and alcohol can affect the risk of CRC. An alternative strategy for preventing CRC is use of a chemopreventive supplement that provides higher individual exposure to nutrients than what can be obtained from the diet. These include calcium, vitamin D, folate, n-3 polyunsaturated fatty acids, and phytochemicals. Several intervention trials have shown that these dietary chemopreventives have positive protective effects on development and progression CRC. Research on chemoprevention with phytochemicals that possess anti-inflammatory and/or, anti-oxidative properties is still in the preclinical phase. Intentional weight loss by bariatric surgery has not been effective in decreasing long-term CRC risk. Physicians should perform dietary education for patients who are at high risk of cancer for changing their dietary habits and behaviour. An increased understanding of the role of individual nutrients linked to the intestinal micro-environment and stages of carcinogenesis would facilitate the development of the best nutritional formulations for preventing CRC.
... 3,4 It has also been found to be safe in human clinical trials; for example, oral curcumin improved the general health of colorectal cancer patients through enhanced p53 expression in tumor cells, leading to tumor cell apoptosis. 5 Garcea et al showed that oral administration of curcumin aided the pharmacologically effective levels in malignant colorectal tissues. 6 Many molecular mechanisms have been proposed to account for the tumor-suppressive effect of curcumin, including inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity, 7 inhibition of apoptosis signal-regulating kinase 1, 8 inhibition of the reactive oxygen species-dependent mitochondrial signaling pathway, 9 and upregulation of α1-antitrypsin. ...
Curcumin is a major component of turmeric with promising tumor-suppressive activity; however, its underlying molecular mechanisms need to be investigated further. We aimed to investigate the mechanisms of curcumin on the proliferation and migration of lung cancer cells. To confirm that, A549 lung cancer cells were cultured in vitro with or without curcumin; the effect of curcumin on cell proliferation was evaluated using the cell counting kit-8 assay, and its effect on cell migration was evaluated using a wound-healing assay. The results suggested that curcumin treatment inhibited the proliferation and migration of A549 cells, but these effects were alleviated when autophagy was inhibited by small interfering RNA that targets ATG5 or autophagy inhibitor 3-methyladenine. Similarly, inactivation of extracellular signal-regulated kinase 1/2 (ERK1/2) also attenuated the effects of curcumin on A549 cells. Collectively, our data suggested that curcumin induces autophagy via activating the ERK1/2 pathway and the autophagy is important for the inhibiting effect of curcumin in lung adenocarcinoma cells.
It is well-established that both communicable and non-communicable diseases present significant challenges to global healthcare. A substantial proportion, approximately 85%, of these diseases can be attributed to environmental factors. Consequently, adopting a healthy lifestyle can serve as a preventative measure for the majority of these ailments. Research conducted over the past few decades has provided valuable insights into the biological properties of various natural sources, including fruits, vegetables, spices, and millets, as well as their bioactive constituents, with the aim of improving human health. Numerous bioactive compounds, commonly referred to as nutraceuticals, have been isolated from these natural sources. Compounds such as curcumin, piperine, resveratrol, isothiocyanates, epigallocatechin gallate (EGCG), quercetin, sulphoraphane, among others, have demonstrated significant disease-preventive and therapeutic properties against a wide spectrum of human ailments. These assertions are supported by extensive preclinical and clinical studies. Consequently, these nutraceutical agents hold immense potential for the prevention and treatment of diseases. Therefore, the present chapter aims to explain the significance of select nutraceuticals and their applications in promoting human well-being.
Cancer is one of the primary causes of human disease and death, with high morbidity and mortality rates. Chemotherapy, one of the most common therapeutic techniques, functions through a variety of mechanisms, including the production of apoptosis and the prevention of tumor development. Herbal medicine has been the subject of numerous investigations due to its potential as a valuable source of innovative anti-cancer products that target multiple protein targets and cancer cell genomes. Curcumin, a polyphenol that is the major bioactive ingredient of turmeric, exhibits pharmacological and biological efficacy with antioxidant, anti-inflammatory, anticancer, cardioprotective, neuroprotective, and hypoglycemic activity in humans and animals. Recent research suggests that curcumin changes noncoding RNA (ncRNA), such as long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), in various types of cancers. Both circRNAs and lncRNAs are ncRNAs that can epigenetically modulate the expression of multiple genes via post-transcriptional regulation. In this study, we outline curcumin’s activities in modulating signaling pathways and ncRNAs in various malignancies. We also described curcumin’s regulatory function, which involves blocking carcinogenic lncRNAs and circRNAs while increasing tumor-suppressive ones. Furthermore, we intend to demonstrate how ncRNAs and signaling pathways interact with each other across regulatory boundaries to gain a better understanding of how curcumin fights cancer and create a framework for its potential future therapeutic uses.
Understanding the molecular signaling pathways of colorectal cancer (CRC) can be accepted as the first step in treatment strategy. Permanent mTOR signaling activation stimulates the CRC process via various biological processes. It supplies the survival of CRC stem cells, tumorigenesis, morbidity, and decreased response to drugs in CRC pathogenesis. Therefore, inhibition of the mTOR signaling by numerous bioactive components may be effective against CRC. The study aims to discuss the therapeutic capacity of various polyphenols, terpenoids, and alkaloids on CRC via the PI3K/Akt/mTOR pathway. The potential molecular effects of bioactive compounds on the mTOR pathway's upstream and downstream targets are examined. Each bioactive component causes various physiological processes, such as triggering free radical production, disruption of mitochondrial membrane potential, cell cycle arrest, inhibition of CRC stem cell migration, and suppression of glycolysis through mTOR signaling inhibition. As a result, carcinogenesis is inhibited by inducing apoptosis and autophagy. However, it should be noted that studies are primarily in vitro dose‐dependent treatment researchers. This study raises awareness about the role of phenolic compounds in treating CRC, contributing to their future use as anticancer agents. These bioactive compounds have the potential to be developed into food supplementation to prevent and treat various cancer types including CRC. This review has the potential to lead to further development of clinical studies. In the future, mTOR inhibition by applying several bioactive agents using advanced drug delivery systems may contribute to CRC treatment with 3D cell culture and in vivo clinical studies.
Introduction
Type 2 diabetes mellitus is characterized by chronically elevated blood sugar levels associated with disruption of the inflammatory and oxidative state and dyslipidemia. Curcumin is a highly pleiotropic molecule with hypoglycemic, hypolipidemic, anti-inflammatory, and antioxidant properties. The aim of this study was to evaluate the effects of curcumin on the liver of streptozotocin-induced diabetic rats.
Materials and Methods
Thirty-two adult male rats were used in the study. The rats were divided into four groups: Control (C), Diabetes (D), Curcumin (CUR), and Diabetes + Curcumin (D + CUR) ( n = 8). The groups given curcumin were given 60 mg/kg curcumin by gavage once a day during the 14-day study period. At the end of the experiment, biochemical, stereological, histological, and immunohistochemical analyses were performed on blood and liver samples taken from rats sacrificed.
Results
After curcumin treatment in diabetic rats, there was a significant decrease in blood glucose levels, hepatic markers, and levels of thiobarbituric acid reactive substances ( P < 0.01). Furthermore, a significant increase in enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase was observed after treatment ( P < 0.01). It was determined that curcumin decreased the apoptotic index and the number of dual-nucleated hepatocytes in the liver, and provided support for liver regeneration ( P < 0.01).
Discussion and Conclusion
Based on the findings of this study, it can be concluded that curcumin has the potential to protect against hyperglycemia-induced oxidative stress and apoptosis in liver cells, and also induces regeneration in damaged liver.
Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related mortality worldwide. The efficacy of chemotherapy agents in CRC treatment is often limited due to toxic side effects, heterogeneity of cancer cells, and the possibility of chemoresistance which promotes cancer cell survival through several mechanisms. Combining chemotherapy agents with natural compounds like curcumin, a polyphenol compound from the Curcuma longa plant, has been reported to overcome chemoresistance and increase the sensitivity of cancer cells to chemotherapeutics. Curcumin, alone or in combination with chemotherapy agents, has been demonstrated to prevent chemoresistance by modulating various signaling pathways, reducing the expression of drug resistance-related genes. The purpose of this article is to provide a comprehensive update on studies that have investigated the ability of curcumin to enhance the efficacy of chemotherapy agents used in CRC. It is hoped that it can serve as a template for future research on the efficacy of curcumin, or other natural compounds, combined with chemotherapy agents to maximize the effectiveness of therapy and reduce the side effects that occur in CRC or other cancers.
Background Curcumin, a polyphenolic compound extracted from turmeric, has emerged as a promising natural anticancer agent due to its potent bioactive properties. However, its clinical application has been overdue by challenges such as limited bioavailability and stability. Nanoemulsion-based delivery systems have emerged as a viable strategy to address the limitations of curcumin. These systems offer enhanced solubility, absorption, and efficacy of curcumin, thereby improving its therapeutic potential in cancer treatment. This review comprehensively examines the use of curcumin nanoemulsions as anticancer agents, focusing on various formulation strategies employed to optimize their physicochemical properties. Additionally, it explores the pharmacokinetic profile of curcumin nanoemulsions and their therapeutic efficacy in different cancer models. Furthermore, the review delves into the underlying mechanisms of action responsible for curcumin's anticancer effects within nanoemulsion formulations. Moreover, it provides a concise overview of patented formulations, ongoing clinical trials, and commercially available products, all serving to substantiate the efficacy and applicability of curcumin in cancer therapy. In conclusion, this review underscores the potential of curcumin nanoemulsions as promising candidates for cancer therapy. Despite current challenges, such as limited clinical translation, the review emphasizes the importance of translational research and personalized medicine approaches in advancing the clinical application of curcumin nanoemulsions. Overall, this comprehensive overview serves as a valuable resource for researchers and clinicians seeking to connect the therapeutic benefits of curcumin nanoemulsions in cancer treatment.
Cancer remains a leading cause of death worldwide, and current cancer drugs often have high costs and undesirable side effects. Additionally, the development of drug resistance can reduce their effectiveness over time. Natural products have gained attention as potential sources for the treatment and prevention of various diseases. Curcumin, an extract from turmeric (Curcuma longa), is a natural phenolic compound with diverse pharmacological properties, including antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, antiprotozoal, antidiabetic, antivenom, antiulcer, anticarcinogenic, antimutagenic, anticoagulant, and antifertility activities. Given the increasing interest in curcumin for cancer prevention, this review aims to comprehensively examine clinical trials investigating the use of curcumin in different types of cancer. Additionally, effective techniques and approaches to enhance the bioavailability of curcumin are discussed and summarized. This review article provides insights into the properties of curcumin and its potential as a future anticancer drug.
Cancer is one of the leading causes of death in the world. Curcuma longa, also known as turmeric, has been traditionally used for the treatment and prevention of various conditions. There has been a growing interest in exploring the potential anticancer properties of C. longa and its bioactive compound, curcumin. Curcumin has been found to exhibit a broad spectrum of anticancer effect by inducing programmed cell death, inhibiting the growth and proliferation of tumors, and suppressing angiogenesis. Its anticancer effect has been reported in many different types of cancer. However, the effectiveness of curcumin is hampered by its poor bioavailability when administered orally. This chapter reviews comprehensively about the anticancer properties of C. longa, mechanisms of anticancer activity of curcumin and update knowledge on the anticancer effect of curcumin in various cancers. Moreover, this chapter discusses about the challenges and future prospects of curcumin in cancer treatment.
The curry powder spices turmeric (Curcuma longa L.), which contains curcumin (diferuloylmethane), an orange-yellow chemical. Polyphenols are the most commonly used sources of curcumin. It combats oxidative stress and inflammation in diseases, such as hyperlipidemia, metabolic syndrome, arthritis, and depression. Most of these benefits are due to their anti-inflammatory and antioxidant properties. Curcumin consumption leads to decreased bioavailability, resulting in limited absorption, quick metabolism, and quick excretion, which hinders health improvement. Numerous factors can increase its bioavailability. Piperine enhances bioavailability when combined with curcumin in a complex. When combined with other enhancing agents, curcumin has a wide spectrum of health benefits. This review evaluates the therapeutic potential of curcumin with a specific emphasis on its approach based on molecular signaling pathways. This study investigated its influence on the progression of cancer, inflammation, and many health-related mechanisms, such as cell proliferation, apoptosis, and metastasis. Curcumin has a significant potential for the prevention and treatment of various diseases. Curcumin modulates several biochemical pathways and targets involved in cancer growth. Despite its limited tissue accumulation and bioavailability when administered orally, curcumin has proven useful. This review provides an in-depth analysis of curcumin's therapeutic applications, its molecular signaling pathway-based approach, and its potential for precision medicine in cancer and human health.
Tumor angiogenesis is the formation of new blood vessels to support the growth of a tumor. This process is critical for tumor progression and metastasis, making it an attractive approach to cancer therapy. Natural products derived from plants, animals, or microorganisms exert anti-angiogenic properties and can be used to inhibit tumor growth and progression. In this review, we comprehensively report on the current status of natural products against tumor angiogenesis from four perspectives until March 2023: 1) the role of pro-angiogenic factors and antiangiogenic factors in tumor angiogenesis; 2) the development of anti-tumor angiogenesis therapy (monoclonal antibodies, VEGFR-targeted small molecules, and fusion proteins); 3) the summary of anti-angiogenic natural agents, including polyphenols, polysaccharides, alkaloids, terpenoids, saponins and their mechanisms of action; 4) the future perspectives of anti-angiogenic natural products (bioavailability improvement, testing of dosage and side effects, combination use, and discovery of unique natural-based compounds). Our review aims to better understand the potential of natural products for drug development in inhibiting tumor angiogenesis and further aid the effective transition of these outcomes into clinical trials.
Despite substantial advancements in curative modern medicine in the last few decades, cancer risk and casualty rates have continued to mount globally. The exact reason for cancer's onset and progression is still unknown. However, skeletal and functional abnormalities in the genetic code are assumed to be the primary cause of cancer. Many lines of evidences reported that some medicinal plants can be utilized to curb cancer cell proliferation with a safe, fruitful, and cost-efficient perspective. Curcuminoids, isolated from Curcuma longa, have gotten a lot of focus due to their anticancer potential as they reduce tumor progression, invasion, and dissemination. Further, they modulated signal transduction routes like MAPK, PI3K/Akt/mTOR, JAK/STAT, and Wnt/β-catenin, etc., and triggered apoptosis as well as actuated autophagy in malignant cells without altering the normal cells, thus preventing cancer progression. Besides, Curcuminoids also regulate the function and expression of anti-tumor and carcinogenic miRNAs. Clinical studies also reported the therapeutic effect of Curcuminoids against various cancer through decreasing specific biomarkers like TNF-α, Bcl-2, COX-2, PGE2, VEGF, IκKβ, and various cytokines like IL-12p70, IL-10, IL-2, IFN-γ levels and increasing in p53 and Bax levels. Thus, in the present review, we abridged the modulation of several signal transduction routes by Curcuminoids in various malignancies, and its modulatory role in the initiation of tumor-suppressive miRNAs and suppression of the oncogenic miRNAs are explored. Additionally, various pharmacokinetic approaches have been projected to address the Curcuminoids bioavailability like the use of piperine as an adjuvant; nanotechnology-based Curcuminoids preparations utilizing Curcuminoids analogues are also discussed.
Curcumin, a natural polyphenol, derived from Curcuma longa L. is extensively studied by various researchers across the globe and has established its immense potential in the management of several disorders at clinical level. The underlying mechanism of curcumin involves regulation of various molecular targets, namely, inflammatory cytokines, transcription factor, apoptotic genes, growth factors, oxidative stress biomarkers, and protein kinases. In clinical trials, curcumin as an adjuvant has significantly boost‐up the efficacy of many proven drugs in the management of arthritis, neurodegenerative disorder, oral infection, and gastrointestinal disorders. Moreover, clinical studies have suggested curcumin as an appropriate candidate for the prevention and/or management of various cancers via regulation of signaling molecules including NF‐kB, cytokines, C‐reactive protein, prostaglandin E2, Nrf2, HO‐1, ALT, AST, kinases, and blood profiles. This article highlights plethora of clinical trials that have been conducted on curcumin and its derivatives in the management of several ailments. Besides, it provides recent updates to the investigators for conducting future research to fulfill the current gaps to expedite the curcumin utility in clinical subjects bearing different pathological states.
Introduction:
Curcumin is a naturally occurring compound that has antioxidant properties, acts as a hepatoprotective, and lowers lipid peroxidation. However, curcumin's low solubility and bioavailability are its primary drawbacks and prevent its use as a therapeutic agent. In this study, curcumin nanoparticles will be created using the ultrasonic-assisted extraction method, and their effectiveness against paracetamol-induced changes in ALT, AST, SOD, MDA, and TNF-α will be compared to that of pure curcumin.
Purpose:
This study aimed to determine the hepatoprotective effect of curcumin nanoparticles in paracetamol-induced rats as a model for liver injury.
Methods:
Thirty-six male Wistar rats, aged 6 to 8 weeks, with a minimum weight of 120 grams, were used in an experimental laboratory investigation with a post-test-only group design. Rats in each group received 100 mg/kgBW pure curcumin, 100 mg/kgBW curcumin nanoparticles, and 50 mg/kgBW curcumin nanoparticles for 7 days before paracetamol induction. On day 8, 300 mg/kgBW of paracetamol was intraperitoneally injected to cause liver damage. One of the groups received NAC as an antidote 10 hours after paracetamol induction. Detection of ALT and AST using a Chemistry Analyzer. ELISA approach for the detection of SOD, MDA, and TNF-α. The Roenigk score was calculated by two examiners after the liver histopathology preparations were stained using the Hematoxylin-Eosin method. Post hoc analyses were performed after the One Way Annova and Kruskal Wallis tests to examine the data.
Results:
According to PSA results, the smallest formula that formed curcumin nanoparticles (10.2 nm) was 8 g of curcumin formula mixed with a mixture of Tween 20 4.5 ml, Kolliphor EL 1.5 ml, Propylene Glycol 1.5 ml, and Capryol 90 1 ml for 21 minutes using an ultrasonic process. MDA and TNF-α levels, as well as the liver's histological Roenigk score, were significantly lower in the 100 mg/kgBB pure curcumin group (C100) when compared to the model group (model). The levels of AST, MDA, TNF-α, and the liver histopathology score were significantly lower in the 100 mg/kgBB (NC100) and 50 mg/kgBB (NC50) curcumin nanoparticle groups compared to the model group (model) and pure curcumin group (C100) (p< 0.05).
Conclusion:
Curcumin nanoparticles showed better hepatoprotective ability than pure curcumin.
Background: Colorectal cancer is the most common malignancy in humans, and it is predicted that 145,600 new cases will be diagnosed in the United States by 2019. The bioactive properties of curcuminoids and their synthetic analogs, especially their performance with an anticancer approach in different cancer cell line models, are of interest. In vivo and in vitro studies show their anticancer activity against colon cancer cell lines. Methods: In this descriptive-analytical study, colorectal cancer cells of the Caco2 cell line were cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. After calculating the IC 50, the cells were exposed to logarithmic concentrations of curcumin (curcumin) 10, 100, and 500 µg/mL for 24 hours. Finally, the effect of the toxicity of materials and low-power laser combined with melanin was measured by the MTT assay test. Results: The changes in the survival rate of colorectal cancer cells show the effect of curcumin on cell proliferation that is completely dependent on concentration and time. Calculating the survival percentage of cancer cells after treatment with different concentrations for 24, 48, and 72 hours showed that the decrease in viable cells compared to the control sample was significant (P < 0.001). Conclusions: The results showed that the use of curcumin either alone or together with a low-power laser could improve the treatment efficiency against colon cancer. The present review highlights the mechanism of synergistic effect and new delivery methods to improve curcumin's therapeutic potential.
Regarding the multimechanistic nature of cancers, current chemo- or radiotherapies often fail to eradicate disease pathology, and frequent relapses or resistance to therapies occur. Brain malignancies, particularly glioblastomas, are difficult-to-treat cancers due to their highly malignant and multidimensional biology. Unfortunately, patients suffering from malignant tumors often experience poor prognoses and short survival periods. Thus far, significant efforts have been conducted to discover novel and more effective modalities. To that end, modulation of the ubiquitin-proteasome system (UPS) has attracted tremendous interest since it affects the homeostasis of proteins critically engaged in various cell functions, for example, cell metabolism, survival, proliferation, and differentiation. With their safe and multimodal actions, phytochemicals are among the promising therapeutic tools capable of turning the operation of various UPS elements. The present review, along with an updated outline of the role of UPS dysregulation in multiple cancers, provided a detailed discussion on the impact of phytochemicals on the UPS function in malignancies, especially brain tumors.
Abstract: The diarylheptanoid curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione] is one of the phenolic pigments responsible for the yellow colour of turmeric (Curcuma longa L.). This phytochemical has gained much attention in recent years due to its therapeutic potential in cancer. A range of drug delivery approaches have been developed to optimise the pharmacokinetic profile of curcumin and ensure that it reaches its target sites. Curcumin exhibits numerous biological effects, including anti-inflammatory, cardioprotective, antidiabetic, and anti-aging activities. It has also been extensively studied for its role as a cancer chemopreventive and anticancer agent. This review focusses on the role of curcumin in targeting the cell signalling pathways involved in cancer, particularly via modulation of growth factors, transcription factors, kinases and other enzymes, pro-inflammatory cytokines, and pro-apoptotic and anti-apoptotic proteins. It is hoped that this study will help future work on the potential of curcumin to fight cancer.
Cancer is considered as the major public health scourge of the 21st century. Though remarkable strides were made for developing targeted therapeutics, these therapies suffer from lack of efficacy, high cost, and debilitating side effects. Therefore, the search for safe, highly efficacious, and affordable therapies is paramount for establishing a treatment regimen for this deadly disease. Curcumin, a known natural, bioactive polyphenol compound from the spice turmeric (Curcuma longa), has been well documented for its wide range of pharmacological and biological activities. A plethora of literature indicates its potency as an anti-inflammatory and anti-cancer agent. Curcumin exhibits anti-neoplastic attributes via regulating a wide array of biological cascades involved in mutagenesis, proliferation, apoptosis, oncogene expression, tumorigenesis, and metastasis. Curcumin has shown a wide range of pleiotropic anti-proliferative effects in multiple cancers and is a known inhibitor of varied oncogenic elements, including NF-κB, c-myc, cyclin D1, Bcl-2, VEGF, COX-2, NOS, TNF-α, interleukins, and MMP-9. Further, curcumin targets different growth factor receptors and cell adhesion molecules involved in tumor growth and progression, making it a most promising nutraceutical for cancer therapy. To date, curcumin-based therapeutics have completed more than 50 clinical trials for cancer. Though creative experimentation is still elucidating the immense potential of curcumin, systematic validation by proper randomized clinical trials warrants its transition from lab to bedside. Therefore, this chapter summarizes the outcome of diverse clinical trials of curcumin in various cancer types
Gastrointestinal cancer (GIC) poses a serious threat to human health globally. Curcumin (CUR), a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, has shown reliable anticancer function and low toxicity, thereby offering broad research prospects. Numerous studies have demonstrated the pharmacological mechanisms underlying the effectiveness of CUR against GIC, including the induction of apoptosis and autophagy, arrest of the cell cycle, inhibition of the epithelial–mesenchymal transition (EMT) processes, inhibition of cell invasion and migration, regulation of multiple signaling pathways, sensitization to chemotherapy and reversal of resistance to such treatments, and regulation of the tumor survival environment. It has been confirmed that CUR exerts its antitumor effects on GIC through these mechanisms in vitro and in vivo. Moreover, treatment with CUR is safe and tolerable. Newly discovered types of regulated cell death (RCD), such as pyroptosis, necroptosis, and ferroptosis, may provide a new direction for research on the efficacy of CUR against GIC. In this review, we discuss the recently found pharmacological mechanisms underlying the effects of CUR against GIC (gastric and colorectal cancers). The objective is to provide a reference for further research on treatments against GIC.
Respiratory depression is the opioid adverse effect feared most by physicians. This may hinder adequate dosing in cancer pain. The study was conducted to examine the respiratory function of patients with advanced cancer receiving significant doses (>100 mg/24 h) of oral morphine.
Consecutive pain-free hospice inpatients with advanced cancer receiving high-dose immediate-release oral morphine were evaluated. A single assessment of respiratory rate (RR), arterial blood gas (ABG), and peak flow rate (PFR) was made at assumed morphine steady state. Venous blood was drawn for a trough morphine plasma level.
Of 31 patients who consented to examination, 20 completed the study assessment; 12 had chronic bronchitis. The median morphine dose was 30 mg 4-hourly (range 20 to 90 mg). Only one patient had evidence of ventilatory impairment.
Morphine does not commonly cause chronic ventilatory impairment when given in this way in this population even in the presence of pre-existing or concurrent respiratory disease. Oral morphine given repeatedly in individualized dosage is a safe and efficacious analgesic in the majority of those with advanced cancer.
Food allergy and chronic intestinal inflammation are common in western countries. The complex of antigen/IgE is taken up into the body from the gut lumen with the aid of epithelial cell-derived CD23 (low affinity IgE receptor II) that plays an important role in the pathogenesis of intestinal allergy. This study aimed to elucidate the role of mast cell on modulation of antigen/IgE complex transport across intestinal epithelial barrier.
Human intestinal epithelial cell line HT29 cell monolayer was used as a study platform. Transepithelial electric resistance (TER) and permeability to ovalbumin (OVA) were used as the markers of intestinal epithelial barrier function that were recorded in response to the stimulation of mast cell-derived chemical mediators.
Conditioned media from naïve mast cell line HMC-1 cells or monocyte cell line THP-1 cells significantly upregulated the expression of CD23 and increased the antigen transport across the epithelium. Treatment with stem cell factor (SCF), nerve growth factor (NGF), retinoic acid (RA) or dimethyl sulphoxide (DMSO) enhanced CD23 expression in HT29 cells. Conditioned media from SCF, NGF or RA-treated HMC-1 cells, and SCF, NGF, DMSO or RA-treated THP-1 cells enhanced immune complex transport via enhancing the expression of the CD23 in HT29 cells and the release of inflammatory mediator TNF-α. Nuclear factor kappa B inhibitor, tryptase and TNF-α inhibited the increase in CD23 in HT29 cells and prevents the enhancement of epithelial barrier permeability.
Mast cells play an important role in modulating the intestinal CD23 expression and the transport of antigen/IgE/CD23 complex across epithelial barrier. (Tu YH, Oluwole C, Struiksma S, Perdue MH, Yang PC. Mast cells modulate transport of CD23/IgE/antigen complex across human intestinal epithelial barrier.
Recent evidence suggests that antiangiogenic therapy is sensitive to p53 status in tumors, implicating a role for p53 in the
regulation of angiogenesis. Here we show that p53 transcriptionally activates the α(II) collagen prolyl-4-hydroxylase [α(II)PH]
gene, resulting in the extracellular release of antiangiogenic fragments of collagen type 4 and 18. Conditioned media from
cells ectopically expressing either p53 or α(II)PH selectively inhibited growth of primary human endothelial cells. When expressed
intracellularly or exogenously delivered, α(II)PH significantly inhibited tumor growth in mice. Our results reveal a genetic
and biochemical linkage between the p53 tumor suppressor pathway and the synthesis of antiangiogenic collagen fragments.
The Prognostic Inflammatory Nutritional Index (PINI) is a simple scoring system that has been used to evaluate nutritional status and prognosis in critically ill patients. The PINI has never been evaluated in advanced cancer. Fifty consecutive patients with advanced cancer, weight loss, and anorexia were studied. C-reactive protein (CRP), albumin, pre-albumin, interleukin-6 (IL-6), and alpha 1-acid glycoprotein (AAG) were evaluated. The individual values for AAG, CRP, and IL-6 were markedly elevated. In contrast to albumin and prealbumin, CRP levels were very high. The PINI was significantly elevated, and higher than reported in critically ill intensive care patients. Elevated IL-6 levels correlated with high PINI and CRP values. CRP, IL-6, and PINI should be considered in future research on nutritional status and prediction of prognosis in advanced cancer.
The prognostic effect of weight loss prior to chemotherapy was analyzedusing data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.
Much research has addressed the association between provider case volume and mortality. We systematically reviewed this association in 96 primary studies involving over one million patients with oesophageal, gastric, hepatic, pancreatic, colonic or rectal cancer, among whom over 70,000 deaths were recorded. Most studies addressed the relationship between hospital surgical case volume and short-term peri-operative mortality. Few studies have addressed the impact of surgeon case volume or evaluated long-term survival as an outcome. Common methodological limitations in estimating magnitude of a volume-related effect were failure to control for potential important confounders, post-hoc categorisation of provider volume and unit of analysis errors.
We found a large volume effect for most gastrointestinal cancers: with each doubling of hospital case volume the odds of peri-operative death decreased by 0.1 to 0.23. This effect was apparent for case volumes ranging from fewer than ten to several hundred per year, with no clear threshold levels. We calculated that between 10 and 50 patients per year, depending on cancer type, need to be moved from a ‘low volume’ hospital to a ‘high volume’ hospital in order to prevent one additional volume-associated peri-operative death. Despite these findings, a number of large studies found no apparent association between hospital volume and peri-operative mortality. The heterogeneity of results from individual studies calls into question the validity of case volume as a proxy for care quality, and leads us to conclude that more direct quality measures and the validity of their use to inform policy should be explored.
The authors systematically reviewed the association between provider case volume and mortality in 101 publications involving greater than 1 million patients with esophageal, gastric, hepatic, pancreatic, colon, or rectal cancer, of whom more than 70,000 died. The majority of studies addressed the relation between hospital surgical case volume and short-term perioperative mortality. Few studies addressed surgeon case volume or evaluated long-term survival outcomes. Common methodologic limitations were failure to control for potential confounders, post hoc categorization of provider volume, and unit of analysis errors. A significant volume effect was evident for the majority of gastrointestinal cancers; with each doubling of hospital case volume, the odds of perioperative death decreased by 0.1 to 0.23. The authors calculated that between 10 and 50 patients per year, depending on cancer type, needed to be moved from a “low-volume” hospital to a “high-volume” hospital to prevent 1 additional volume-associated perioperative death. Despite this, approximately one-third of all analyses did not find a significant volume effect on mortality. The heterogeneity of results from individual studies calls into question the validity of case volume as a proxy for care quality, and leads the authors to conclude that more direct quality measures and the validity of their use to inform policy should also be explored. CA Cancer J Clin 2009;59:192–211. © 2009 American Cancer Society.
Curcumin is a polyphenol derived from Curcuma longa. Over the last few years, a number of studies have provided evidence of its main pharmacological properties including chemosensitizing, radiosensitizing, wound healing activities, antimicrobial, antiviral, antifungical, immunomodulatory, antioxidant and anti-inflammatory. More recent data provide interesting insights into the effect of this compound on cancer chemoprevention and chemotherapy. In fact, preclinical studies have shown its ability to inhibit carcinogenesis in various types of cancer including colorectal cancer (CRC). Curcumin has the capacity of interact with multiple molecular targets affecting the multistep process of carcinogenesis. Also, curcumin is able to arrest the cell cycle, to inhibit the inflammatory response and the oxidative stress and to induce apoptosis in cancer cells. Likewise, it has been shown to possess marked antiangiogenic properties. Furthermore, curcumin potentiates the growth inhibitory effect of cyclo-oxygenase (COX)-2 inhibitors and traditional chemotherapy agents implicating another promising therapy regimen in the future treatment of CRC. However, its clinical advance has been hindered by its short biological half-life and low bioavailability after oral administration. This review is intended to provide the reader an update of the bioavailability and pharmacokinetics of curcumin and describes the recently identified molecular pathways responsible of its anticancer potential in CRC.
Paramount to the maintenance of normal tissue homeostasis is the induction of programmed cell death, otherwise known as apoptosis. Several disease states, including cancer, are characterized by an inability to remove unwanted cells due to a failure to commit to apoptosis. What is more, apoptosis is the central functional response behind many agents utilized in the treatment of cancer. Many of these antitumorigenic agents rely on the activation of the tumor suppressor p53. As the physiological "guardian of the genome," p53's normal function is to sense stressed or damaged cells and arrest proliferation, allowing time for cellular repair. However, if the damage is excessive, cells are removed prior to the onset of malignancy through apoptosis. Current chemotherapeutic strategies manipulate this property by damaging cells and turning on p53's transcriptional function, which consequently upregulates the expression of proapoptotic proteins such as Puma. We have also demonstrated that Puma is capable of inducing apoptosis independent of p53. In this regard, defects in the apoptotic machinery or in p53 function itself lead to a resistant phenotype that in cancer results in chemotherapeutic failure, and more often than not, poor prognosis. This chapter describes protocols for the determination of p53-dependent and -independent apoptosis utilizing primary cells from genetically altered mice.
The introduction of novel agents targeted to specific molecular features of cancer cells promises more options and marked improvements in efficacy for treatment of colon cancer. This overview of clinical studies describes the effects of administering the targeted agents bevacizumab, cetuximab, and panitumumab, also known as monoclonal antibodies, to treat metastatic colorectal cancer (mCRC) patients. All three targeted agents have been approved for use by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. Bevacizumab has been shown to extend survival when used in combination with irinotecan and 5-fluorouracil-based chemotherapy, and the addition of cetuximab to irinotecan and 5-fluorouracil-based chemotherapy overcomes irinotecan resistance. Cetuximab and panitumumab are both efficacious among refractory mCRC patients with wild-type KRAS tumors. Other targeted agents, for example, the tyrosine kinase inhibitors erlotinib, gefitinib, sunitinib, and vatalanib (PTK787/ZK 222584), are currently in various stages of clinical development.
Many data support the beneficial effect of n-3 polyunsaturated fatty acids (PUFAs) as chemopreventive and chemotherapeutic agents in the treatment of several chronic pathologies including cancer. Different molecular mechanisms have been proposed to explain their effects, including alterations in arachidonic acid oxidative metabolism and metabolic conversion of n-3 PUFAs to novel discovered bioactive derivatives; modification of oxidative stress; changes in cell membrane fluidity and structure and altered metabolism and function of membrane proteins. Considerable knowledge has been recently gathered on the possible beneficial effects of n-3 PUFAs administered in combination with different antineoplastic drugs and radiotherapy against melanoma, leukemia, neuroblastoma, and colon, breast, prostate, and lung cancer. The efficacy of these combinations has been demonstrated both in vivo and in vitro, and clinical trials have also been conducted. The aim of this review is to analyze all the n-3 PUFA combinations investigated so far, their efficacy, and the possible molecular mechanisms involved. It would be highly auspicable that the detailed analysis of the literature in this field could further support the common use of n-3 PUFAs in combination with other chemopreventive agents and warrant more clinical investigations designed to test the effectiveness of n-3 PUFA treatments coupled with conventional antineoplastic therapies.
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), is extracted from the plant Curcuma longa. It has cytotoxic effects and induces apoptosis in many human cancer cells but the molecular mechanisms are not fully understood. In the present study, we evaluated the effects of curcumin on human breast cancer MDA-MB-231 cells. The cytotoxic effects of curcumin on MDA-MB-231 cells were measured by MTT assay. The percentages of cell cycle were determined by flow cytometry. The protein expressions of p21, 53, Bax and Bcl-2 were examined by Western blotting. The results show that curcumin inhibits the proliferation of MDA-MB-231 cells and induces G2/M arrest in a dose-dependent manner. Curcumin increased the protein expressions of p21 and Bax, but decreased the protein expression of p53 and Bcl-2 in MDA-MB-231 cells. Our results show that one molecular mechanism of curcumin inhibits the proliferation of MDA-MB-231 cells either through up-regulating p21 expression and then inducing apoptosis, or through up-regulating the Bax to Bcl-2 ratio and then inducing apoptosis. Our results also show that curcumin inhibits the migratory activity of MDA-MB-231 cells through down-regulating the protein expression of NF-kappaBp65. Accordingly, the therapeutic potential of curcumin for breast cancer deserves further study.
Cancer cachexia-associated weight loss is poorly understood; energetically demanding tissues (eg, organ and tumor mass) and resting energy expenditure (REE) are reported to increase with advanced cancer.
The objective was to quantify the potential contribution of increasing masses of energetically demanding tissues to REE with colorectal cancer cachexia progression.
A longitudinal computed tomography (CT) image review was performed to quantify organ size (liver, including metastases, and spleen) and peripheral tissues (skeletal muscle and adipose tissue) during colorectal cancer cachexia progression (n = 34). Body composition was prospectively evaluated by CT and dual-energy X-ray absorptiometry, and REE was determined by indirect calorimetry in advanced colorectal cancer patients (n = 18).
Eleven months from death, the liver (2.3 +/- 0.7 kg) and spleen (0.32 +/- 0.2 kg) were larger than reference values. One month from death, liver weight increased to 3.0 +/- 1.5 kg (P = 0.010), spleen showed a trend to increase (P = 0.077), and concurrent losses of muscle (4.2 kg) and fat (3.5 kg) (P < 0.05) were observed. The estimated percentage of fat-free mass (FFM) occupied by the liver increased from 4.5% to 7.0% (P < 0.001). The most rapid loss of peripheral tissues and liver and metastases gain occurred within 3 mo of death. A positive linear relation existed between liver mass and measured whole-body REE (r(2) = 0.35, P = 0.010); because liver accounted for a larger percentage of FFM, measured REE . kg FFM(-1) . d(-1) increased (r(2) = 0.35, P = 0.010).
Increases in mass and in the proportion of high metabolic rate tissues, including liver and tumor, represented a cumulative incremental REE of approximately 17,700 kcal during the last 3 mo of life and may contribute substantially to cachexia-associated weight loss.
The infection with Friend murine leukemia virus (FMuLv) is being used as a retrovirus infection model for searching the potential anti-viral medicinal preparations or establishing new treatment strategies. In the present study we have evaluated the inhibitory effect of three non-toxic antiviral natural compounds namely berberine, curcumin or picroliv against FMuLv induced erythroleukemia in BALB/c mice. To understand the effect of these compounds in the initiation and progression of leukemia we did a series of analysis, which include hematological and biochemical parameters, histopathological evaluations of the liver and the spleen and expression analysis of selected genes such as Bcl-2, p53, p45NFE2, Raf-1, Erk-1, IFNgamma receptor and erythropoietin in spleen. The treatment with berberine, curcumin or picroliv were found to (a) elevate the life span of leukemia harboring animals by more than 60 days; (b) decreased the anemic condition which was highly prevalent in FMuLv alone treated group; (c) histopathological evaluations showed that the compounds tested here inhibited the massive leukemic cell infiltrations to sinusoidal spaces in spleen; (d) decrease the expression of Bcl-2, Raf-1, Erk-1 IFNgamma receptor and erythropoietin; (e) induce the expression of p53. Overall, our results suggest that berberine, curcumin and picroliv were able to suppress the progression of leukemia induced by FMuLv and further support their chemopreventive potential against virally induced cancers.
Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clinical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare complete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the oncosuppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bacteriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolytic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strongly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics. It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers.
Curcumin, a natural compound derived from tumeric, has been shown to induce apoptosis in the leukemic cell line K562 and other cancer cell lines. However, it is unknown whether curcumin also has an inhibitory effect on BCR-ABL-expressing B-lymphoid cells. We tested whether curcumin has an inhibitory effect on BCR-ABL B-cell acute lymphoblastic leukemia (B-ALL) in vitro and in vivo.
Pre-B cells isolated from B6 mice expressing wild-type BCR-ABL (B6p210) and T315I mutant (B6T315I) were cultured in serial concentration of curcumin. Cultured cells were analyzed by automated cell counter, flow cytometry, western blotting, and transcription factor arrays. B-ALL was induced by transplantation of MSCV-GFP-p210 transduced donor marrow in lethally irradiated Balb/c mice. Diseased mice were treated with placebo or curcumin until death of the mice. Diseased mice were analyzed by flow cytometric and histopathological analyses.
Curcumin inhibited the proliferation of B6p210 and B6T315I cells at concentration as low as 10 muM and induced apoptosis of the cells at concentrations of 30 muM. Using western blots and transcription factors arrays, we showed that curcumin decreased NF-kappaB levels and increased p53 levels. Curcumin decreased c-Abl levels in cells expressing the wild, but not the mutant, BCR-ABL oncogene. Curcumin treatment resulted in a statistically significant improved survival in diseased mice along with decreasing white blood and GFP cell counts.
Curcumin is effective against leukemic cells expressing p210 BCR-ABL and T315I BCR-ABL and holds promise in treating BCR-ABL-induced B-ALL.
The present study aims to access the effects of sophora alkaloids on the production of pro-inflammatory cytokines and evaluate their therapeutic efficiency on cachexia. The comparative study showed that all sophora alkaloids tested here, including matrine, oxymatrine, sophocarpine, sophoramine, and sophoridine, inhibited TNF-alpha and IL-6 production in both RAW264.7 cells and murine primary macrophages, and sophocarpine showed the most potent inhibitory effect among them. Quantification of TNF-alpha and IL-6 mRNA in RAW264.7 cells by real-time RT-PCR revealed that both sophocarpine and matrine suppressed TNF-alpha and IL-6 expression and sophocarpine has stronger suppressing potency than matrine. Inoculation (s.c.) of colon26 adenocarcinoma cells into BALB/c mice induced cachexia, as evidenced by progressive weight loss, reduction in food intake, wasting of gastrocnemius muscle and epididymal fat, and increase in serum levels of TNF-alpha and IL-6. Administration of 50 mg/kg/d sophocarpine or matrine for 5 days from the onset of cachexia did not inhibit the tumor growth but resulted in attenuation of cachexia symptoms. Furthermore, sophocarpine and matrine decreased the serum levels of TNF-alpha and IL-6, and sophocarpine showed a better therapeutic effect than matrine. These results suggest that sophocarpine and matrine exert anti-cachectic effects probably through inhibition of TNF-alpha and IL-6.
The prognostic effect of weight loss prior to chemotherapy was analyzed using data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.
During the past 20 years, the flowering plant Arabidopsis thaliana has been adopted as a model organism by thousands of biologists. This community has developed important tools, resources and experimental approaches that have greatly stimulated plant biological research. Here, we review some of the key events that led to the uptake of Arabidopsis as a model plant and to the growth of the Arabidopsis community.
Cachexia — the massive (up to 80%) loss of both adipose tissue and skeletal muscle mass — is a significant factor in the poor performance status and high mortality rate of cancer patients. Although this metabolic defect has been known since cancer was first studied, it is only recently that major advances have been made in the identification of catabolic factors that act to destroy host tissues during the cachectic process. Although anorexia is frequently present, depression of food intake alone seems not to be responsible for the wasting of body tissues, as nutritional supplementation or pharmacological manipulation of appetite is unable to reverse the catabolic process — particularly with respect to skeletal muscle. However, recent clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise.
The development of cancer cachexia is perhaps the most common manifestation of advanced malignant diseases and has been recognized as a poor prognostic sign. The abnormalities associated with the condition include progressive weight loss, anorexia, asthenia, and anemia. The degree of cachexia is inversely correlated with the survival time of the patient and always implies a poor prognosis. Currently there is no established mechanism for cancer cachexia, but the severe metabolic disturbances and marked alterations in carbohydrate, lipid, and protein metabolism in the host finally lead to an increased energy deficiency. Weight loss, the key feature of cachexia, is due to a reduction of food intake, an increase in energy expenditure, or a combination of the two. A variety of changes in nutrient metabolism have been described in patients with cancer cachexia. Patients frequently exhibit a relative glucose intolerance and insulin resistance with increased activity of the Cori cycle. The cancer-bearing state affects protein synthesis and breakdown in different tissues of the body in a different manner. An acute-phase protein response can be presented in a significant proportion of patients with cancer with disease progression. A variety of proinflammatory cytokines appears to play a role in aspects of cachexia and a complex network of cytokines in combination with other factors might be involved. Aside from potential humoral mediators of cachexia, tumor-derived biologically active molecules have been reported recently.
Food allergy accounts for significant morbidity. The etiology and immune mechanisms of food allergy, however, have remained poorly understood. In this study, we aimed to determine the role of T-cell immunoglobulin-domain and mucin-domain (TIM)-4, a recently identified member of cell surface molecules, in the pathogenesis of intestinal allergy in a murine model.
We report that TIM-4 as well as costimulatory molecules were up-regulated in intestinal mucosal dendritic cells by in vitro or in vivo exposure to Staphylococcus enterotoxin B (SEB). SEB-conditioned intestinal dendritic cells loaded with a food macromolecule ovalbumin (OVA) induced potent OVA-specific T-helper (Th)2 lymphocyte responses in vitro and such Th2 responses were inhibited completely by TIM-4 blockade.
In vivo exposure to both SEB and OVA resulted in OVA-specific Th2 differentiation and intestinal allergic responses including increased serum immunoglobulin E and Th2 cytokine levels, activation of OVA-specific Th2 cells detected both ex vivo and in situ, and mast cell degranulation. Of importance, in vivo abrogation of TIM-4 or its cognate ligand TIM-1 by using a polyclonal antibody remarkably dampened Th2 differentiation and intestinal allergy.
Our study thus identifies TIM-4 as a novel molecule critically required for the development of intestinal allergy.
Cancer cachexia is associated with weight loss, poor nutritional status, and systemic inflammation. Accurate nutritional support for patients is calculated on resting energy expenditure (REE) measurement or prediction. The present study evaluated the agreement between measured and predicted REE (mREE and pREE, respectively) and the influence of acute phase response (APR) on REE.
Thirty-six patients with cancer were divided into weight-stable (WS; weight loss <2%) and weight-losing (WL; weight loss >5%) patients. Measured REE was measured by indirect calorimetry and adjusted for fat-free mass (FFM). The Bland-Altman approach was used to assess the agreement between mREE and pREE from the Harris-Benedict equations (HBE). Blood levels of C-reactive protein were assessed.
There was no difference in mREE between groups (WS 1677 +/- 273, WL 1521 +/- 305) even when mREE was adjusted for FFM (WS 1609 +/- 53, WL 1589 +/- 53). In WL patients, FFM-adjusted REE correlated with blood C-reactive protein levels (r = 0.471, P = 0.048). HBEs tend to underestimate REE in both groups.
WL and WS patients with cancer had similar REEs but were different in terms of APR. APR could contribute to weight loss through enhancing REE. In a clinical context, HBE was in poor agreement with mREE in both groups.
Although traditional medicines have been used for thousands of years, for most such medicines neither the active component nor their molecular targets have been very well identified. Curcumin, a yellow component of turmeric or curry powder, however, is an exception. Although inhibitors of cyclooxygenase-2, HER2, tumor necrosis factor, EGFR, Bcr-abl, proteosome, and vascular endothelial cell growth factor have been approved for human use by the United States Food and Drug Administration (FDA), curcumin as a single agent can down-regulate all these targets. Curcumin can also activate apoptosis, down-regulate cell survival gene products, and up-regulate p53, p21, and p27. Although curcumin is poorly absorbed after ingestion, multiple studies have suggested that even low levels of physiologically achievable concentrations of curcumin may be sufficient for its chemopreventive and chemotherapeutic activity. Thus, curcumin regulates multiple targets (multitargeted therapy), which is needed for treatment of most diseases, and it is inexpensive and has been found to be safe in human clinical trials. The present article reviews the key molecular mechanisms of curcumin action and compares this to some of the single-targeted therapies currently available for human cancer.
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New mech-anisms and therapeutic potential of curcumin for colorectal can-cer
- Villegas I S Sá-Fidalgo
- Alarcó
Villegas I, Sá-Fidalgo S, Alarcó ?, de la Lastra C. New mech-anisms and therapeutic potential of curcumin for colorectal can-cer. Mol Nutr Food Res 2008;52(9):1040–1061.