Tocotrienols fight cancer by targeting multiple cell signaling pathways.
Tocotrienols fight cancer by targeting multiple cell signaling pathways.
Abstract: Cancer cells are distinguished by several distinct characteristics, such as self-sufficiency in growth signal, resistance to growth inhibition, limitless replicative potential, evasion of apoptosis, sustained angiogenesis, and tissue invasion and metastasis. Tumor cells acquire these properties due to the dysregulation of multiple genes and associated cell signaling pathways, most of which are linked to inflammation. For that reason, rationally designed drugs that target a single gene product are unlikely to be of use in preventing or treating cancer. Moreover, targeted drugs can cause serious and even life-threatening side effects. Therefore, there is an urgent need for safe and effective promiscuous (multitargeted) drugs. “Mother Nature” produces numerous such compounds that regulate multiple cell signaling pathways, are cost effective, exhibit low toxicity, and are readily available. One among these is tocotrienol, a member of the vitamin E family, which has exhibited anticancer properties. This review summarizes data from in vitro and in vivo studies of the effects of tocotrienol on nuclear factor-κB, signal transducer and activator of transcription (STAT) 3, death receptors, apoptosis, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hypoxia-inducible factor (HIF) 1, growth factor receptor kinases, and angiogenic pathways.
Kannappan R, et al. Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes & nutrition. 2012 Vol 7, Issue 1. Pp 43-52
Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E.
Abstract: The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (γ and δ) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated “highly metabolized” T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.
Viola V et al. Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E. Genes & nutrition. 2012 Vol 7, Issue 1. Pp 29-41
Tocotrienols and breast cancer: the evidence to date.
Abstract: Breast cancer is the second most frequent cancer affecting women worldwide after lung cancer. The toxicity factor associated with synthetic drugs has turned the attention toward natural compounds as the primary focus of interest as anticancer agents. Vitamin E derivatives consisting of the well-established tocopherols and their analogs namely tocotrienols have been extensively studied due to their remarkable biological properties. While tocopherols have failed to offer protection, tocotrienols, in particular, α-, δ-, and γ-tocotrienols alone and in combination have demonstrated anticancer properties. The discovery of the antiangiogenic, antiproliferative, and apoptotic effects of tocotrienols, as well as their role as an inducer of immunological functions, not only reveals a new horizon as a potent antitumor agent but also reinforces the notion that tocotrienols are indeed more than antioxidants. On the basis of a transcriptomic platform, we have recently demonstrated a novel mechanism for tocotrienol activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate a high affinity of specific forms of tocotrienols for ERβ, but not for ERα. Moreover, we have demonstrated that specific tocotrienols increase ERβ translocation into the nucleus which, in turn, activates the expression of estrogen-responsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERβ cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERβ is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. Furthermore, a recently concluded clinical trial seems to suggest that tocotrienols in combination with tamoxifen may have the potential to extend breast cancer-specific survival.
Nesaretnam K, et al. Tocotrienols and breast cancer: the evidence to date. Genes & nutrition. 2012 Vol. 7 Issue 1 Pp 3-9
Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells.
Abstract: Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Identifying novel chemotherapeutic and chemopreventive approaches is critical in the prevention and treatment of cancers such as pancreatic cancer. Vitamin E succinate (VES) is a redox-silent analog of the fat-soluble vitamin alpha-tocopherol. In the present study, we explored the antiproliferative action of VES and its effects on inhibitor of apoptosis proteins in pancreatic cancer cells. We show that VES inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. Further, we demonstrate that VES downregulates the expression of survivin and X-linked inhibitor of apoptosis proteins. The apoptosis induced by VES was augmented by siRNA-mediated inhibition of survivin in PANC-1 cells. In summary, our results suggest that VES targets survivin signaling and induces apoptosis in pancreatic cancer cells.
Patacsil D et al. Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells. Genes & nutrition. 2012 Vol. 7 Issue 1 Pp 83-9
To determine the effects of curcumin, (-)-epigallocatechin-3-gallate (EGCG), lovastatin, and their combinations on inhibition of esophageal cancer
METHODS: Esophageal cancer TE-8 and SKGT-4 cell lines were subjected to cell viability methyl thiazolyl tetrazolium and tumor cell invasion assays in vitro and tumor formation and growth in nude mouse xenografts with or without curcumin, EGCG and lovastatin treatment. Gene expression was detected using immunohistochemistry and Western blotting in tumor cell lines, tumor xenografts and human esophageal cancer tissues, respectively.
RESULTS: These drugs individually or in combinations significantly reduced the viability and invasion capacity of esophageal cancer cells in vitro. Molecularly, these three agents reduced the expression of phosphorylated extracellular-signal-regulated kinases (Erk1/2), c-Jun and cyclooxygenase-2 (COX-2), but activated caspase 3 in esophageal cancer cells. The nude mouse xenograft assay showed that EGCG and the combinations of curcumin, EGCG and lovastatin suppressed esophageal cancer cell growth and reduced the expression of Ki67, phosphorylated Erk1/2 and COX-2. The expression of phosphorylated Erk1/2 and COX-2 in esophageal cancer tissue specimens was also analyzed using immunohistochemistry. The data demonstrated that 77 of 156 (49.4%) tumors expressed phosphorylated Erk1/2 and that 121 of 156 (77.6%) esophageal cancers expressed COX-2 protein. In particular, phosphorylated Erk1/2 was expressed in 23 of 50 (46%) cases of esophageal squamous cell carcinoma (SCC) and in 54 of 106 (50.9%) cases of adenocarcinoma, while COX-2 was expressed in 39 of 50 (78%) esophageal SCC and in 82 of 106 (77.4%) esophageal adenocarcinoma.
CONCLUSION: The combinations of curcumin, EGCG and lovastatin were able to suppress esophageal cancer cell growth in vitro and in nude mouse xenografts, these drugs also inhibited phosphorylated Erk1/2, c-Jun and COX-2 expression.
In the current study, we demonstrated that curcumin, EGCG, lovastatin, and their combinations can significantly reduce the viability and invasion capacity of esophageal cancer cells in vitro. Nevertheless, they were much less effective in vivo in nude mouse xenografts, especially curcumin and lovastatin individually. At the molecular level, these three agents individually or in combination inhibited the expression of phosphorylated Erk1/2, c-Jun, and COX-2 and induced caspase 3 expression in esophageal cancer cells in vitro. In nude mouse xenografts, the expression of p-Erk1/2 and COX-2 was downregulated by these three drugs, especially their combinations. We also analyzed the expression of phosphorylated Erk1/2 and COX-2 in tissue specimens from esophageal cancer patients. The data showed that 49.4% of esophageal cancers expressed phosphorylated Erk1/2 and that 77.6% of cancers expressed COX-2 protein. These data suggest that curcumin, EGCG, and lovastatin inhibit esophageal cancer cell growth in vitro and in nude mouse xenografts possibly through the suppression of phosphorylated Erk1/2, c-Jun and COX-2 expression.
Previous studies have shown the chemopreventive activity of EGCG in suppressing carcinogenesis in several organs, including the esophagus[29,34]. Molecularly, EGCG can suppress the mitotic signal transduction pathway, e.g., inhibit Erk1/2 phosphorylation and anti-AP-1 activity[38]. A recent study demonstrated that EGCG induced a concentration- and time-dependent reversal of hypermethylation of RAR-β2 in esophageal cancer cell lines, resulting in re-expression of RAR-β2[33]. Furthermore, curcumin has been shown to inhibit different cancers at the initiation, promotion, and progression stages in animal models[31,32,38]. Curcumin also suppressed growth and induced apoptosis in numerous types of cancer cells in vitro[38,39]. Although the defined mechanisms of its action require further study, its efficacy appears to be related to the induction of glutathione and glutathione-S-transferase activity, inhibition of lipid peroxidation and arachidonic acid metabolism, and suppression of oxidative DNA adduct formation[32,38,39]. Curcumin can inhibit the activation of NF-κB and the expression of c-Jun, c-Fos, c-Myc, Erk1/2, COX-2, PI3K, Akt, CDKs, and iNOS[31,35,38,39]. Curcumin was also able to suppress cigarette smoke-induced NF-κB activation and COX-2 expression in head and neck SCC and non-small-cell lung cancer cells[31,32]. In esophageal cancer, dietary curcumin can inhibit chemically-induced esophageal carcinogenesis in mice and rats[28,40]. In addition, the statin family of drugs has shown cancer chemopreventive effects[41]. Statins can trigger some tumor cells to undergo apoptosis in vitro and suppress tumor growth in vivo[30,37,41]. Statins also have an antimetastatic property, which is evident in their suppression of tumor cells invasiveness in Matrigel, as well as in animal experiments[42]. In addition, statins, especially at high concentrations, can inhibit capillary tube formation by endothelial cells in vitro and in vivo[33,44]. The effects of statins are thought to be mediated through inhibition of Ras and RhoA activity[41]. Based on these previous studies and reports, we determined the effects of their combinations on suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts by targeting the RAR-β2/Erk1/2/AP1/COX-2 pathway[3]. Indeed, our current study has demonstrated the effects of their combinations in vitro. Molecularly, these three agents were able to regulate the expression of this gene pathway in vitro and in vivo in nude mice. Nevertheless, individually curcumin and lovastatin had no effect on tumor formation and growth in nude mice, even when the highest dose possible was used. This may be due to the bioavailability of curcumin and the induction of COX-2 expression by high dose lovastatin, reported previously[30,39]. However, the current study did not show the induction of COX-2 expression by high dose lovastatin in esophageal cancer in vitro and in nude mice, similar to that seen in prostate cancer[30].
However, there are some limitations in the current study. Firstly, we showed that these three drugs regulated gene expression of the RAR-β2/Erk1/2/AP1/COX-2 pathway, however, previous studies also showed that as chemoprevention agents, these drugs target multiple genes and their pathways in different cancers. Thus, further study is needed to determine the mechanisms of action of these drugs in human cancers. Furthermore, we used established esophageal cancer cell lines to determine the chemopreventive effects of these agents in this study, the results of which may be quite different in comparison to those in premalignant cells in vivo. The xenograft assay tested the effects of these agents in suppressing tumor initiation and growth, but not tumor development per se, although the xenograft assay did test the bioavailability of these agents in vivo. In addition, we did not test whether the doses of these three agents are clinically achievable, and to reduce costs, we utilized a single dose of each agent and their combinations.
Source:
Ye F, Zhang G-H, Guan B-X, Xu X-C. To determine the effects of curcumin, (-)-epigallocatechin-3-gallate (EGCG), lovastatin, and their combinations on inhibition of esophageal cancer. World journal of gastroenterology: WJG. 2012 Vol. 18 Issue 2. Pp 126-35
Referencs:
29. Li ZG, Shimada Y, Sato F, Maeda M, Itami A, Kaganoi J, Komoto I, Kawabe A, Imamura M. Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. Int J Oncol. 2002;21:1275–1283. [PubMed]
30. Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC. Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention. Carcinogenesis. 2005;26:785–791. [PubMed]
31. Aggarwal S, Takada Y, Singh S, Myers JN, Aggarwal BB. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. Int J Cancer. 2004;111:679–692. [PubMed]
32. Shishodia S, Potdar P, Gairola CG, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis. 2003;24:1269–1279. [PubMed]
33. Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003;63:7563–7570. [PubMed]
34. Wang ZY, Wang LD, Lee MJ, Ho CT, Huang MT, Conney AH, Yang CS. Inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by green and black tea. Carcinogenesis. 1995;16:2143–2148. [PubMed]
35. Rafiee P, Nelson VM, Manley S, Wellner M, Floer M, Binion DG, Shaker R. Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-kappaB. Am J Physiol Gastrointest Liver Physiol. 2009;296:G388–G398. [PubMed]
36. O’Sullivan-Coyne G, O’Sullivan GC, O’Donovan TR, Piwocka K, McKenna SL. Curcumin induces apoptosis-independent death in oesophageal cancer cells. Br J Cancer. 2009;101:1585–1595. [PMC free article] [PubMed]
37. Ogunwobi OO, Beales IL. Statins inhibit proliferation and induce apoptosis in Barrett’s esophageal adenocarcinoma cells. Am J Gastroenterol. 2008;103:825–837. [PubMed]
38. Conney AH. Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the Seventh DeWitt S. Goodman Lecture. Cancer Res. 2003;63:7005–7031. [PubMed]
39. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003;23:363–398. [PubMed]
40. Ushida J, Sugie S, Kawabata K, Pham QV, Tanaka T, Fujii K, Takeuchi H, Ito Y, Mori H. Chemopreventive effect of curcumin on N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. Jpn J Cancer Res. 2000;91:893–898. [PubMed]
41. Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer. 2005;5:930–942. [PubMed]
42. Graaf MR, Richel DJ, van Noorden CJ, Guchelaar HJ. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat Rev. 2004;30:609–641. [PubMed]
43. Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation. 2002;105:739–745. [PubMed]
44. Vincent L, Chen W, Hong L, Mirshahi F, Mishal Z, Mirshahi-Khorassani T, Vannier JP, Soria J, Soria C. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett. 2001;495:159–166. [PubMed]
PHARMACEUTICAL APPROACH OF HERBICEUTICAL FORMULA WITH ANTICANCER PROPERTIES
Concept 1
Tumour cells starve due to blocked anoerobic glucose utility by herbal active component(s): The glucose utility block augments the aerobic energy metabolism in host. The block leads the lactate dehydrogenase inhibition and suppressed cytosolic TCA cycle (2,3 dimethoxy-5-methyl-1,4-benzoquinone (DMBQ) in coenzyme Q10. The blocked glycolysis also favours mitochondrial oxidative function through complex I-IV (example riboflavin, FAD, FMN derivatives)
Concept 2
Oxygen depletion and hypoxia in tumour: High oxygen is not good for tumour cells. High oxygen in tumour cells causes high mitochondrial respiration (where oxygen is a substrate for mitochondrial complex IV) and high alkalinity.
Concept 3
Inhibition of lactate dehydrogenase (LDH-V M4): The LDH plays active role in development of malignancy as enzyme LDH generates product NAD+ and 2 pyruvate molecules from one glucose. Immediately NAD+ is consumed as cofactor of glyceraldehydes-3-phosphate dehydrogenase to push more ATP more production through anaerobic metabolism catalysed by phosphoglycerate/ pyruvate kinase. While pyruvate molecule gets into acetylCoA by pyruvate dehydrogenase in aerobic metabolism.
The neutraceutical composition is widely advocated in cancer therapy based on combination of vitamins, salts, roots and herbs prepared in palatable pharmaceutical carrier as neutraceutical composition initially proposed by Mazzio et al (2007). Alternatively herbiceuticals may be used more efficiently if using in combination with more % of flavones in the mixture as proposed in this paper.
In present paper, herbs are surveyed to demonstrate their benefits in human health and possible use as anti-cancer supplements. The pharmacological action and biochemical mechanisms of herbs are highlighted for their possible effects on tissue and anticancer action. A possible herbal anticancer composition is proposed for make effective anticancer herbal formula. The focus of paper is a comparison of anticancer strengths of different herbs. The toxic effects of herbal over intake are highlighted to show their side effects.
Source:
Sharma R. Recommendations on Herbs and Herbal Formula in Cancer Prevention. The Open Nutraceuticals Journal, 2010, 3, 129-140
Herb Group: (60-90% flavones w/w)
Huai Shan Yao (Dioscorea villosa), xu duan (Dipsacus asper), balm of gilead bud (Populus balsamifera), bakuchi seed (Cymopsis psoralidoides), chan shan (Dichroa febrifuga), di fu zi (Kochia scoparia), huang shui qie (Solanum xanthocarpum), hu zhang (Polugonum Cuspidatum), da hui xiang (?) (Terminalia arjuna), babul chall bark (Acacia Arabica), Sweet Myrrh (Acacia farnesiana) zhu ye (?) (Phyllanthus niruri), Garcinia fruit (Garcinia Cambogia), Vitex (Vitex agnus-castus), Dragons Blood (Calamus draco), rou dou kou (Myristica fragans), White sage (Salvia apian), red sandal wood (Pterocarpus santalinu)
Mazzio E, Soliman K. Nutraceutical Composition and Method of use for treatment / prevention of cancer 2007 US patent 2007/0248693.
Is Radiation Therapy A Necessity?
by Ralph W. Moss, PhD
Sunday, 28 November 2010
A standard treatment for early-stage breast cancer is to remove the tumor via lumpectomy and then follow that with radiation therapy and the drug, tamoxifen. But a report presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO) has called this approach into question. Researchers at Massachusetts General Hospital, Boston, studied women over the age of 70 who had estrogen receptor positive (ER+) tumors that were removed by lumpectomy. The subjects were randomly assigned to receive either tamoxifen alone or tamoxifen plus radiation therapy.
After more than 10 years, the women who received just the tamoxifen fared about the same as those who also received radiation. Although radiation resulted in fewer recurrences in the affected breast, the chance of being free from distant metastases was 95% with tamoxifen alone vs. 93% for tamoxifen plus radiation. The 10-year breast-cancer-specific survival was 98% with tamoxifen alone vs. 96% with radiation. The overall survival was 63% with tamoxifen alone vs. 61% with radiation added, i.e., it was slightly higher when women did not receive radiation.
The authors themselves concluded that “the addition of radiation does not impact survival, distant disease free survival, breast cancer specific survival or breast conservation” (Hughes 2010).
The Web site Breastcancer.org states that “these results shouldn’t be used to make treatment decisions for women younger than 70.” Fair enough. But many readers are bound to wonder whether radiation is worthwhile for women under the age of 70. That wasn’t addressed in this study. Radiation’s main purpose after breast surgery is to prevent recurrences, and it does a pretty good job at that. However, its impact on survival is not as great as some people suppose. Even the authoritative Perez and Brady textbook refers to “the lack of survival benefit associated with breast irradiation….” Needless to say, a lot of questions remain about the actual survival benefit of radiation therapy, including some indications for which it is now commonly used.
References:
Hughes KS, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer. 2010 ASCO Annual Meeting. Oral Abstract Session, Breast Cancer – Local-Regional and Adjuvant Therapy. J Clin Oncol 28:15s, 2010 (suppl; abstr 507)
Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N. Engl. J. Med. 2004;351(10):971-977.
Perez, Carlos and Brady, Luther, eds. Principles and Practice of Radiation Oncology, Philadelphia: LWW, 4th ed., 2004, p. 1371.
Reported Intake of Selected Micronutrients and Risk of Colorectal Cancer
Aim: The impact of micronutrient intake and colorectal cancer (CRC) risk is poorly understood. The objective of this study was to evaluate the associations of selected micronutrients with risk of incident CRC in study participants from Newfoundland, Labrador (NL) and Ontario (ON), Canada.
Materials and Methods: We conducted a population-based study among 1760 case participants and 2481 age- and sex-matched control participants. Information on diet and other lifestyle factors were measured using a food frequency questionnaire and a personal history questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, controlling for covariables.
Results: Highest compared to lowest quartile intakes of certain micronutrients were associated with lower risk of CRC, including: calcium (from food and supplements (FS), OR=0.59; 95% CI=0.45-0.77, and from food only (FO): OR=0.76, 95% CI=0.59-0.97), vitamin C (FS:OR=0.67; 95%CI:0.51-0.88), vitamin D (FS: OR=0.73; 95% CI: 0.57-0.94, FO: OR=0.79, 95% CI=0.62-1.00), riboflavin (FS: OR=0.61; 95% CI=0.47-0.78, and folate (FS: OR=0.72; 95% CI=0.56-0.92). Higher risk of CRC was observed for iron intake (highest versus lowest quintiles: OR=1.34, 95% CI=1.01-1.78).
Conclusion: This study presents evidence that dietary intake of calcium, vitamin D, vitamin C, riboflavin and folate are associated with a lower risk of incident CRC and that dietary intake of iron may be associated with a higher risk of the disease.
Source:
Sun Z, Zhu Y, Wang PP, et al. Reported Intake of Selected Micronutrients and Risk of Colorectal Cancer: Results from a Large Population-based Case–control Study in Newfoundland, Labrador and Ontario, Canada. Anticancer Research February 2012 vol. 32 no. 2 687-696
Effects of Silybinin on the Pharmacokinetics of Tamoxifen and Its Active Metabolite, 4-Hydroxytamoxifen in Rats
The effects of silybinin, an antioxidant, on the pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. A single dose of tamoxifen was administered intravenously (2 mg/kg) and orally (10 mg/kg) without or with silybinin (0.5, 2.5 and 10 mg/kg) to rats. Silybinin significantly altered the pharmacokinetics of orally administered tamoxifen. Compared to those in the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of tamoxifen were significantly (p<0.05 for 2.5 mg/kg, p<0.01 for 10 mg/kg) increased by 40.2-71.3% and 45.2-78.6%, respectively, with silybinin. Consequently, the absolute bioavailability (AB) of tamoxifen in the presence of silybinin (2.5 and 10 mg/kg) was 31.1-38.1%, which was significantly enhanced (p<0.05) compared to that in the oral control group (22.2%). Moreover, the relative bioavailability (RB) of tamoxifen was 1.40- to 1.72-fold greater than that in the control group. Silybinin (10 mg/kg) significantly increased the AUC0-∞ (p<0.05, 40.0%) of 4-hydroxytamoxifen, but the metabolite-parent ratio (MR) of 4-hydroxytamoxifen was significantly altered (p<0.05 for 10 mg/kg), implying that the formation of 4-hydroxytamoxifen was considerably affected by silybinin. The enhanced bioavailability of tamoxifen by silybinin might be due to the promotion of intestinal absorption in the small intestine and the reduction of first-pass metabolism of tamoxifen in the small intestine and in the liver. If these results are confirmed in clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with silybinin or silybinin-containing dietary supplements.
Kim C-S, Choi S-J, Park C-Y, et al. Anticancer Research January 2010 vol. 30 no. 1 79-85