title: Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention.
abstract: A recent meta-analysis examining long-term mortality in subjects who participated in controlled studies evaluating the impact of daily aspirin on vascular risk, has concluded that aspirin confers substantial protection from cancer mortality. Remarkably, low-dose aspirin was as effective as higher-dose regimens; hence this protection may be achievable with minimal risk. There is reason to believe that this protection stems primarily from inhibition of cox-2 in pre-neoplastic lesions. Since safe aspirin regimens can only achieve a partial and transitory inhibition of cox-2, it may be feasible to complement the cancer-protective benefit of aspirin with other measures which decrease cox-2 expression or which limit the bioactivity of cox-2-derived PGE2. Oxidative stress boosts cox-2 expression by up-regulating activation of NF-kappaB and MAP kinases; NADPH oxidase activation may thus promote carcinogenesis by increasing cox-2 expression while also amplifying oxidant-mediated mutagenesis. A prospective cohort study has observed that relatively elevated serum bilirubin levels are associated with a marked reduction in subsequent cancer mortality; this may reflect bilirubin's physiological role as a potent inhibitor of NADPH oxidase. It may be feasible to mimic this protective effect by supplementing with spirulina, a rich source of a phycobilin which shares bilirubin's ability to inhibit NADPH oxidase. Ancillary antioxidant measures - phase 2 inducing phytochemicals, melatonin, N-acetylcysteine, and astaxanthin - may also aid cox-2 down-regulation. The cancer protection often associated with high-normal vitamin D status may be attributable, in part, to the ability of the activated vitamin D receptor to decrease cox-2 expression while promoting PGE2 catabolism and suppressing the expression of PGE2 receptors. Diets with a relatively low ratio of omega-6 to long-chain omega-3 fats may achieve cancer protection by antagonizing the production and bioactivity of PGE2. Growth factors such as IGF-I increase cox-2 expression by several complementary mechanisms; hence, decreased cox-2 activity may play a role in the remarkably low mortality from "Western" cancers enjoyed by Third World cultures in which systemic growth factor activity was minimized by quasi-vegan diets complemented by leanness and excellent muscle insulin sensitivity. Practical strategies for achieving a modest degree of calorie restriction may also have potential for down-regulating cox-2 expression while decreasing cancer risk. Soy isoflavones, linked to reduced cancer risk in Asian epidemiology, may suppress cox-2 induction by activating ERbeta. In aggregate, these considerations suggest that a comprehensive lifestyle strategy targeting cox-2 expression and bioactivity may have tremendous potential for cancer prevention.
authors: NutriGuard Research, Inc., 1051 Hermes Ave., Encinitas, CA 92024, USA. markfmccarty@gmail.com
authors: Mark F
authors: MF
authors: McCarty
mesh_terms: D001241:Aspirin; D001663:Bilirubin; D031204:Caloric Restriction; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D015525:Fatty Acids, Omega-3; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007529:Isoflavones; D019255:NADPH Oxidases / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000502:physiology*; D053545:Spirulina; D014807:Vitamin D
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D015525:Fatty Acids, Omega-3; D007529:Isoflavones; D014807:Vitamin D; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D015232:Dinoprostone; D001241:Aspirin; D001663:Bilirubin