Supplementing the diet of tumor-bearing mice or rats with oils containing (n-3) (omega-3) or with purified (n-3) fatty acids has slowed the growth of various types of cancers, including lung, colon, mammary, and prostate. The efficacy of cancer chemotherapy drugs such as doxorubicin, epirubicin, CPT-11, 5-fluorouracil, and tamoxifen, and of radiation therapy has been improved when the diet included (n-3) fatty acids. Some potential mechanisms for the activity of (n-3) fatty acids against cancer include modulation of eicosanoid production and inflammation, angiogenesis, proliferation, susceptibility for apoptosis, and estrogen signaling. In humans, (n-3) fatty acids have also been used to suppress cancer-associated cachexia and to improve the quality of life. In one study, the response to chemotherapy therapy was better in breast cancer patients with higher levels of (n-3) fatty acids in adipose tissue [indicating past consumption of (n-3) fatty acids] than in patients with lower levels of (n-3) fatty acids. Thus, in combination with standard treatments, supplementing the diet with (n-3) fatty acids may be a nontoxic means to improve cancer treatment outcomes and may slow or prevent recurrence of cancer. Used alone, an (n-3) supplement may be a useful alternative therapy for patients who are not candidates for standard toxic cancer therapies.

The results of animal studies have demonstrated that the consumption of omega-3 fatty acids can slow the growth of cancer xenografts, increase the efficacy of chemotherapy and reduce the side effects of the chemotherapy or of the cancer. Molecular mechanisms postulated to contribute to the multiple benefits of omega-3 fatty acids include 1) suppressing the expression of cyclooxygenase-2 in tumors, thus decreasing proliferation of cancer cells and reducing angiogenesis in the tumor; 2) decreasing the expression of AP-1 and ras, two oncogenes implicated in tumor promotion; 3) inducing differentiation of cancer cells; 4) suppressing nuclear factor-kappaB activation and bcl-2 expression, thus allowing apoptosis of cancer cells; and 5) reducing cancer-induced cachexia. It seems reasonable to assume that after appropriate cancer therapy, consumption of omega-3 fatty acids might slow or stop the growth of metastatic cancer cells, increase longevity of cancer patients and improve their quality of life.

Capsaicin, the pungent ingredient of chili peppers, displays potent anti-neoplastic activity in a wide array of human cancer cells. The present manuscript examines the signaling pathways underlying the apoptotic activity of capsaicin in human small cell lung cancer (SCLC) in vitro and in vivo. Studies in neuronal cells show that capsaicin exerts its biological activity via the transient receptor potential vanilloid (TRPV) superfamily of cation-channel receptors. The TRPV family is comprised of six members (TRPV1-6). Capsaicin is an agonist of the TRPV1 receptor. We observed that capsaicin-induced apoptosis in human SCLC cells was mediated via the TRPV receptor family; however it was independent of TRPV1. Surprisingly, the apoptotic activity of capsaicin required the TRPV6 receptor. Depletion of TRPV6 receptor by siRNA methodology abolished the apoptotic activity of capsaicin in SCLC cells. Immunostaining and ELISA showed that TRPV6 receptor was robustly expressed on human SCLC tissues (from patients) and SCLC cell lines but almost absent in normal lung tissues. This correlates with our results that capsaicin induced very little apoptosis in normal lung epithelial cells. The proapoptotic activity of was mediated by the intracellular calcium and calpain pathway. The treatment of human SCLC cells with capsaicin induced increased the activity of calpain 1 and 2 by three-fold relative to untreated SCLC cells. Such calpain activation, in response to capsaicin, was downstream of the TRPV6 receptor. Taken together, our data provide insights into the mechanism underlying the apoptotic activity of capsaicin in human SCLCs.

BackgroundSmall cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays anti-proliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo.Methodology/Principal FindingsBrdU assays and PCNA ELISAs showed that capsaicin displays robust anti-proliferative activity in four human SCLC cell lines. Furthermore, capsaicin potently suppressed the growth of H69 human SCLC tumors in vivo as ascertained by CAM assays and nude mice models. The second part of our study attempted to provide insight into molecular mechanisms underlying the anti-proliferative activity of capsaicin. We found that the anti-proliferative activity of capsaicin is correlated with a decrease in the expression of E2F-responsive proliferative genes like cyclin E, thymidylate synthase, cdc25A and cdc6, both at mRNA and protein levels. The transcription factor E2F4 mediated the anti-proliferative activity of capsaicin. Ablation of E2F4 levels by siRNA methodology suppressed capsaicin-induced G1 arrest. ChIP assays demonstrated that capsaicin caused the recruitment of E2F4 and p130 on E2F-responsive proliferative promoters, thereby inhibiting cell proliferation.Conclusions/SignificanceOur findings suggest that the anti-proliferative effects of capsaicin could be useful in the therapy of human SCLCs.

Walnuts contain components that may slow cancer growth including omega 3 fatty acids, phytosterols, polyphenols, carotenoids, and melatonin. A pilot study was performed to determine whether consumption of walnuts could affect growth of MDA-MB 231 human breast cancers implanted into nude mice. Tumor cells were injected into nude mice that were consuming an AIN-76A diet slightly modified to contain 10% corn oil. After the tumors reached 3 to 5 mm diameter, the diet of one group of mice was changed to include ground walnuts, equivalent to 56 g (2 oz) per day in humans. The tumor growth rate from Day 10, when tumor sizes began to diverge, until the end of the study of the group that consumed walnuts (2.9 +/- 1.1 mm(3)/day; mean +/- standard error of the mean) was significantly less (P > 0.05, t-test of the growth rates) than that of the group that did not consume walnuts (14.6 +/- 1.3 mm(3)/day). The eicosapentaenoic and docosahexaenoic acid fractions of the livers of the group that consumed walnuts were significantly higher than that of the group that did not consume walnuts. Tumor cell proliferation was decreased, but apoptosis was not altered due to walnut consumption. Further work is merited to investigate applications to cancer in humans.

Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BAC) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChR). In this study, we show that human BACs produce acetylcholine (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3), and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs, and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by a7-, a3b2-, and b3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or insulin-like growth factor-II-induced growth of human BACs. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy. Cancer Res; 73(4); 1328-39. Ó2012 AACR.

Epidemiology studies indicate that diet or specific dietary components can reduce the risk for cancer, cardiovascular disease and diabetes. An underlying cause of these diseases is chronic inflammation. Dietary components that are beneficial against disease seem to have multiple mechanisms of action and many also have a common mechanism of reducing inflammation, often via the NFκB pathway. Thus, a plant based diet can contain many components that reduce inflammation and can reduce the risk for developing all three of these chronic diseases. We summarize dietary components that have been shown to reduce cancer risk and two studies that show that dietary walnut can reduce cancer growth and development. Part of the mechanism for the anticancer benefit of walnut was by suppressing the activation of NFκB. In this brief review, we focus on reduction of cancer risk by dietary components and the relationship to suppression of inflammation. However, it should be remembered that most dietary components have multiple beneficial mechanisms of action that can be additive and that suppression of chronic inflammation should reduce the risk for all three chronic diseases.

SummaryThe cancer chemotherapeutic efficacy of the topoisomerase I inhibitor, is often limited by the induction of severe delayed diarrhoea. In animal studies, CPT-11 use is associated with histopathological damage to the mucosa of the small and large intestines. Results from the present study demonstrate that 60 mg CPT-11 per kg body weight (i.v. q4d ϫ 6) halted the growth, but did not cause significant regression, of MCF7 human breast carcinoma xenografts in mice fed a diet containing 7% corn oil. However, when the diet of the MCF7-bearing mice was supplemented with 3% or 6% fish oil, the same CPT-11 treatment caused significant regression of the MCF7 xenograft. Histomorphometric analyses of intestinal mucosa of mice treated with CPT-11 and fed the diet containing 7% corn oil indicated that treatment with CPT-11 induced structural changes in the intestinal mucosa which persisted at least 5 days after the last dose of CPT-11. The intestinal mucosal architecture of mice that were treated with CPT-11 and fed the diets containing fish oil was largely unchanged from the architecture of the group of mice which did not receive CPT-11. These findings indicate that fish oil supplements may be a useful adjunct to CPT-11 treatment.