Nutrition and Cancer From Epidemiology to Biology

Resveratrol is a polyphenol produced by certain plants in response to stress. A major dietary source of resveratrol is red wine. This polyphenol has a multitude of effects on mammalian cells, including inhibiting the proliferation and/or inducing apoptosis in cancer cells. This review focuses on recent insights into the metabolism, cancer-specific activities and molecular pathways of resveratrol action. While much work has been published on resveratrol’s effects on cancer cells in tissue culture, fewer studies have been performed with rodent cancer models. The animal work shows that resveratrol is effective in inhibiting the development or progression of tumors of the prostate, brain and esophagus. An interesting finding in an animal model of pancreatic cancer is the ability of resveratrol to not only inhibit tumor growth, but to also sensitize the tumor to gemcitabine. Analogous to other phytochemicals, resveratrol inhibits multiple signaling pathways including PI-3K/AKT, NF-kB, TGF-β and COX2 mediated signaling. The major metabolites of resveratrol include piceatannol, resveratrol glucuronide and monosulfated dihydroresveratrol. It is not clear if any of these metabolites have biological activity. There are currently three NCI-registered clinical trials with resveratrol. At present there are no published results from these trials. Low bioavailability of resveratrol may limit its in vivo effectiveness. Numerous questions remain to be answered regarding resveratrol’s biologic actions and its potential role in the chemoprevention and/or treatment of cancer.

Capsaicin is an active ingredient of chili peppers. Although traditionally associated with chemopreventive and anti-carcinogenic activity, recent studies have shown that capsaicin has profound anti-neoplastic effects in several types of human cancer cells. The biological activity of capsaicin is mediated by the transient receptor potential vanilloid [TRPV] superfamily of ion channel receptors. Specifically, capsaicin is an agonist of the TRPV1 receptor. The growth-inhibitory properties of capsaicin have been found to be mediated by TRPV1-dependent and independent mechanisms. Experiments in multiple animal models have demonstrated that the anti-cancer activity of capsaicin is not associated with any discomfort or toxicity. The present review summarizes the current knowledge on the growth-inhibitory activity of capsaicin and discusses the signaling pathways underlying its anticancer effects. Future studies involving the design of capsaicin-mimetics with improved selectivity may represent novel strategies in the treatment of human cancers.

The growth of various types of cancers including lung, colon, mammary, and prostate in animal models has been slowed by supplementing the diet of the tumor-bearing mice or rats with oils containing omega-3 (n-3) fatty acids or with purified n-3 fatty acids. 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. A number of potential mechanisms have been identified for the activity of n-3 fatty acids against cancer including modulation of: eicosanoid production and inflammation, angiogenesis, proliferation, susceptibility for apoptosis, estrogen signaling and free radical activity. The response to chemotherapy 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 in one study. Omega-3 fatty acids have also been used to suppress cancer-associated cachexia and improve the quality of life in human studies. Thus, supplementing the diet with n-3 fatty acids may be a nontoxic means to improve the outcome of standard cancer therapies and may slow or prevent recurrence of cancer in patients that are not candidates for standard cancer treatments.

Tea is one of the most widely consumed beverages in the world. Processed from the leaf of Camellia sinensis, teas contain a large number of phytochemicals including four catechins; epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG). These catechins are at much higher levels in green tea compared to black tea. Over the last 20 years tea catechins have shown the potential for use as an adjunct therapy for a number of diseases including diabetes and cancer. This chapter will discuss the potential of green tea catechins in cancer prevention and as an adjunct to chemotherapy. Including the potential molecular mechanisms believed to be involved in regulating cancers.

Vitamin A, the parent compound of retinoids, was first noted for its role in vision. However, discovery of the ability of retinoids to attenuate tumorigenesis gave rise to a new field of research dedicated to elucidating the mechanisms by which retinoids exhibited antitumor activity. Clinically used since the late 1960’s, retinoids comprise a family of structurally similar molecules that exhibit a variety of antitumor effects such as inhibiting cellular proliferation, as well as inducing apoptosis, cell cycle arrest, and differentiation. Much of the early work was strongly focused on signaling pathways influenced by retinoids binding to retinoic acid receptors (RARs). Nonetheless, recent data suggests also receptor-independent mechanisms such as changes in the redox balance within a cell and activation of transcription factors that do not bind the retinoic acid response element. Vitamin A is metabolized into various structural forms such as 9-cis retinoic acid (RA), 13-cis Retinioc Acid, and all-trans Retinioc Acid; additionally, synthetic retinoids have been demonstrated to elicit much of the same effects as the aforementioned endogenous retinoids. Acute promyelocytic leukemia (APL) was one of the first cancers to be successfully treated with 13-cis RA. Complications such as toxicity and drug resistance gave rise to clinical trials using all-trans Retinioc Acid and, although successful in most patients, a few drug resistant cell populations were discovered. Therefore, decades of research have been aimed to gain a better understanding of both receptor and, most recently, non-receptor mediated signaling pathways which may positively influence future strategies in treatment of various tumors.

In this chapter, the impact of lipid molecules on hematopoiesis will be reviewed in a format friendly to those outside the field. The focus of the review is on how dietary fatty acids impact hematopoiesis through changes in differentiation. We begin with a discussion of general hematopoiesis including the concepts of stem and progenitor cells that drive hematopoiesis and the various cell types they produce. We then will discuss the principles of epigenetic gene regulation and differentiation pertinent to hematopoietic stem and progenitor cells. Once these principles have been introduced, we will examine how dietary lipids can impact hematopoietic differentiation. The relationship of epigenetics and dietary lipids to leukemic and preleukemic states will also be explored. We will conclude with a look at how WNT signaling can impact hematopoiesis through epigenetic gene regulation, dietary lipids, and differentiation.

Phytochemicals are now increasingly being used as nutritional supplements to either prevent or treat chronic diseases including cancer. The mechanisms of action of the phytochemicals can range from: inhibiting oxidative stress, apoptosis, inhibiting mitochondrial damage and inhibiting or promoting angiogenesis. The significance of oxidative stress in the etiology of aging and several chronic diseases: including cardiovascular disease, cancer and Alzheimer’s, has given support to the usage of these phytochemicals to inhibit oxidative damage. The complexity of the chemistry involved in oxidative stress damage to cells or tissue adds to the consideration of choice of the phytochemical to combat these effects. Cancer is a multifactorial disease. Epidemiological studies have shown beneficial effects of several phytochemicals in the prevention and treatment of several types of cancer. This chapter will address the role of oxidative stress in cancer and the antioxidant action of some of the most popularly used phytochemicals including-green tea, soy, resveratrol and ellagic acid (flavonoids, polyphenols).

The purpose of this review is to examine the literature to determine what epidemiologic and experimental evidence exists that either supports or denies a role for iron in the etiology of breast cancer, paying particular attention to the dietary heme iron source of red meat. The importance of red meat as a dietary source of iron and the relationship between iron and oxidant stress are introduced. Epidemiologic and experimental studies of the relationship between iron and breast cancer are reviewed. Extant studies involving phase II detoxication gene interactions with red meat consumption and breast cancer or iron-related gene polymorphisms and breast cancer are also reviewed. In conclusion, a model by which red meat may impact breast cancer involving the delivery of dietary iron is proposed and discussed.

Isothiocyanates (ITCs) are phytochemicals produced from the hydrolysis of glucosinolates, which are found at high concentrations in cruciferous vegetables. Vegetables of the Cruciferae family include, among others, broccoli, cauliflower, gardencress, watercress, and cabbage. A number of studies using animal models have suggested that certain ITCs are capable of preventing breast, lung, and prostate carcinogenesis. Additionally, certain ITCs such as sulforaphane (SFN), benzyl (BITC), and phenethyl (PEITC) isothiocyanate have been shown to elicit strong chemotherapeutic properties. SFN, BITC, and PEITC are suggested to target several cellular pathways that inhibit growth, induce apoptosis, and prevent migration, and are presently being investigated for their therapeutic potential. Work on ITCs is progressing quickly from bench to beside, and currently there are several ongoing clinical trials. One study is investigating PEITC’s ability to inhibit lung carcinogenesis, while another trial is investigating how PEITC affects lymphoproliferative disorders, specifically in patients who have received the chemotherapeutic drug, fludarabine. Additionally, a Phase II clinical trial is investigating whether SFN can modulate the level of prostate specific antigen in patients with recurrent prostate cancer. This chapter will give an overview of the previously mentioned ITCs, and their reported ability to inhibit carcinogenesis in vivo and in vitro at three stages: initiation, promotion, and progression.