Food‐based approach to cancer prevention

Abstract

We live in a drug-oriented society that is focused principally on disease treatment rather than disease prevention. Disease treatment is the major focus because, rather than taking measures to prevent disease, most U.S. citizens wait until they become ill and expect a drug to be available to cure them. Witness the alarming increase in obesity in U.S. citizens of all ages and the accompanying increases in cardiovascular disease, diabetes, and cancer, among other diseases. Or the well-established relationship between smoking and multiple diseases including lung cancer and yet approximately 18% of Americans continue to smoke tobacco. There is a strong economic incentive to develop drugs for disease treatment, and thus it is not surprising that this is the major focus of our pharmaceutical industry. It is encouraging, however, that in the past several decades more citizens are becoming aware of alternative measures that can be taken to prevent disease including the consumption of foods and nutraceuticals known to have disease preventative properties. In this commentary, I will discuss an alternative approach to the prevention of cancer using foodstuffs. Because research in my laboratory, and those of my colleagues, has been done with berries, I will focus on our experience with berries as an example of a cancer preventative foodstuff. Much of what is said here with berries could well apply to many other commonly consumed foodstuffs. Along with other scientists whose research had been focused on studies to determine how chemicals cause cancer (chemical carcinogenesis), in the 1980s my laboratory changed direction to studies on the use of chemicals to prevent cancer (cancer chemoprevention). The early leaders in the field of chemoprevention, Drs. Lee Wattenberg, Paul Talalay, and Michael Sporn, advanced the field greatly by conducting research with individual compounds, most of which were either naturally occurring in foods or synthetic derivatives of these food compounds (Sporn, 2011; Talalay, Dinkova-Kostova, & Holtzclaw, 2003; Wattenberg, 1997). My laboratory began its studies with the polyphenolic compound, ellagic acid, which was found to exhibit a spectrum of cancer preventative properties in vitro and in vivo (Maas, Galletta, & Stoner, 1991). Ellagic acid, however, is insoluble in water and most organic solvents and was effective in the diet only when added at high concentrations. Synthetic derivatives of ellagic acid that were either more lipid- or water-soluble were not more effective as chemopreventive agents than ellagic acid itself (unpublished data). In a study to determine dietary sources of ellagic acid, we found that, in fruit, it was present at high concentrations in black and red raspberries (Daniel et al., 1989). We chose to work with black raspberries because they are a specialty crop in Ohio, and we were able to identify a suitable source of berries. Because black raspberries are about 80% water, we decided to remove the water by freeze-drying the berries and then grinding the dried berries into a powder. This resulted in a seven- to eightfold concentration of the ellagic acid and other chemopreventive agents that might be present in the berries. Indeed, chemical analysis showed that multiple putative chemopreventive agents are present in black raspberries (Stoner, 2009), and biofractionation studies indicated that the anthocyanins, and not the ellagitannins, in the berries are responsible for a significant portion of their chemopreventive activity (Hecht et al., 2006; Wang et al., 2009). The fiber component is also bioactive (Wang et al., 2009). Using black raspberry powder as a “food-based” approach to cancer prevention, in preclinical studies, the berries were shown to produce a 30–70% reduction in chemically induced tumors in the rodent oral cavity (Casto et al., 2002), esophagus (Kresty et al., 2001), and colon (Harris et al., 2002) when provided at concentrations of 5 and 10% in a synthetic diet. Subsequent investigations in the laboratories of Drs. Ramesh Gupta and Tatiana Oberyszyn showed that the berries inhibited estrogen-induced mammary cancer in rats and UVB-induced skin cancer in mice, respectively (Aiyer, Srinivasan, & Gupta, 2008; Duncan et al., 2009). Mechanistic studies indicated that the berries reduce the growth rate of premalignant cells and are anti-inflammatory and antiangiogenic, and they stimulate cell differentiation, apoptosis, and the immune response (Chen, Rose, Hwang, Nines, & Stoner, 2006; Kresty et al., 2001; Mallery et al., 2008; Mentor-Marcel et al., 2012; Peiffer et al., 2016; Wang et al., 2009; Zikri et al., 2009). Multiple genes associated with these cellular functions were shown to be modulated protectively by the berries (Chen et al., 2006; Chen, Hwang, Rose, Nines, & Stoner, 2006; Huang et al., 2006; Kresty et al., 2001; Mallery et al., 2008; Stoner et al., 2008; Wang et al., 2009; Zikri et al., 2009). In clinical trials, different formulations of black raspberries were shown to produce histologic regression and partially restore loss of heterozygosity in leukoplakic lesions of the oral cavity (Mallery et al., 2014), reduce the expression of proinflammatory and prosurvival genes in oral squamous cell carcinomas (Knobloch et al., 2016), influence parameters of oxidative stress and increase the expression of glutathione-S-transferase pi (GST-pi) in patients with Barrett's esophagus (Kresty et al., 2016), reduce cell proliferation and angiogenesis and influence DNA methylation of tumor suppressor genes in colorectal tumors (Wang et al., 2011), and cause partial regression of rectal polyps in patients with familial adenomatous polyposis (Wang et al., 2014). Black raspberries contain many compounds with demonstrated chemopreventative activity; therefore, they should exhibit a broad spectrum of chemopreventive effects including protective modulation of key genes involved in signaling pathways associated with cancer development. Because black raspberries are a natural foodstuff, it should be possible to administer them to rodents and humans at relatively high doses without eliciting toxic effects. Indeed, in one study, the powder was administered to familial adenomatous polyposis patients at a concentration of 60 g/day for 9 months with only occasional gastrointestinal disturbances in about 5% of patients. These included either constipation or diarrhea and generally lasted only 1 or 2 days. This is in contrast to clinical trials of multiple individual chemopreventive agents that have been stopped due to unacceptable toxicity or, in some cases, have produced actual increases in cancer occurrence in the treated subjects (Goralczyk, 2009; Lippman et al., 2009; Omenn et al., 1994). There are relatively few studies that have employed whole foods for cancer prevention. Most investigations have used either extracts of foodstuffs or individual compounds present in foods. The elegant studies of Talalay, Kensler, and Fahey with broccoli (Egner et al., 2011; Fahey et al., 2015), including broccoli sprouts, summarized recently in Molecules (Yagishita, Fahey, Dinkova-Kostova, & Kensler, 2019), are another example of the use of a whole food for cancer prevention. Other examples include the use of tomato paste for the prevention of prostate cancer (Edinger & Koff, 2006) and of green tea for the prevention of oral cancer (Ramshankar & Krishnamurthy, 2014). On the whole, however, this has been not a popular approach to chemoprevention due, in part, to concerns related to the identification and standardization of the active components in foods, the reluctance of physicians to conduct clinical trials with agents other than pure drugs, and the lack of financial reward commensurate with drug development. What is needed is for the food industry to provide additional support for research on whole foods that has been shown to increase their sales of the products evaluated if they are found to exhibit chemopreventive effects. Hard science is needed to confirm anecdotal evidence from traditional medicine to provide the public a suitable database from which to make choices on foodstuffs to consume. In my view, this is an area of investigation that deserves more attention.

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