Resveratrol and cancer in Ogg1-Myh deficient mice

The phytoalexin resveratrol is a particularly potent antioxidant and has been reported to be cancer chemopreventive, neuroprotective and to protect the cardiovascular system. However, due to its low bioavailability it has been suggested that its manifold documented positive effects in vitro might be irrelevant. Nevertheless, remarkable in vivo neuroprotective and cancer chemopreventive effects have also been reported and these do call for further studies with this compound. RVs molecular targets and biological effects are strongly concentration, time and tissue dependent. It is therefore unclear which conceivable benefits/utilizations of RV are realistic or illusive. In addition, in vitro studies with RV metabolites, analogs or derivatives suggest that particular structural changes to this molecule can remarkably enhance specific activity or overcome particular limitations (e.g. selective cyclooxygenase inhibition). There is considerable evidence that reactive oxygen species (ROS) contribute to tumorigenesis. The most convincing evidence comes from the development of spontaneous tumors in mice deficient for antioxidant defense (e.g. MnSOD, peroxiredoxins) or oxidative DNA damage repair (e.g. Ogg1 or Mth) enzymes. Besides its radical scavenging properties, RV also induces increased antioxidant enzyme expression/activity (e.g. NQO-1 or heme oxidase 1). Thus it is likely that RV or its analogs might be useful in ROS-related maladies. Nonetheless, RVs potential protective benefits from ROS induced mutagenesis and tumorigenesis have not yet been evaluated in vivo. In addition, almost nothing is known about the effects of RV derivatives or analogs in vivo. The pun reversion is uniquely sensitive in detecting in vivo chemical and physical agents that cause cancer. Meanwhile, Ogg1; Myh double mutant mice represent an ideal model for the accumulation of oxidative DNA damage eventually resulting in tumor formation, as well as, effects on the frequency, latency and multiplicity of oxidative DNA damage induced tumors. Therefore, we propose to study RV and RV analogs for their DNA protective and cancer chemopreventive potential in wild type and oxidative DNA damage repair deficient mice in vitro and in vivo. These experiments will aid in the assessment whether these compounds are suitable chemopreventives in humans.

Resveratrol is a naturally occurring polyphenolic compound found in grapes and wine with a variety of biological and pharmacological properties. Resveratrol is a potent antioxidant and was found to be active in the prevention of cardiovascular and neurodegenerative diseases, inflammation and ischemic injuries. It is also considered a chemopreventive agent by blocking or delaying tumor development through numerous effects at several discrete stages during the process of carcinogenesis. These in vivo effects are observed despite its low bioavailability and rapid clearance from the circulation due to extensive glucuronidation and sulfation in the intestine and liver. Any extrapolation of the resveratrol biotransformation in mice and rats to the human situation is only partly possible as glucuronidation is far more pronounced in the animal model compared to human liver. Interestingly, metabolism of resveratrol is not only species but also organ specific. While in the liver and intestine resveratrol is glucuronidated and sulfated only sulfation could be observed in human breast tumor tissue. Beneficial effects like reduced mutation rates after feeding of resveratrol were already observed before this study in long term animal studies. However, no precise resveratrol dose estimations and resveratrol plasma levels were determined. We used a well-liked hydrationgel (as water substitute) to feed resveratrol to our test animals. This ensured frequent and regular resveratrol uptake (1-2x /h) and resveratrol levels in blood plasma of 0.5-7g/ml. These values result in a significantly increased antioxidative capacity in plasma, in significantly reduced DNA double strand breaks in irradiated lymphocytes (3Gy) and therefore in a clear protective effect. In non-irradiated blood significant differences in DNA double strand breaks were observed between repair-deficient and proficient mice but not between the resveratrol receiving animals and control group. Ogg1; Myh double mutant mice are deficient in the repair of oxidative DNA damage and represent an ideal model for the accumulation of oxidative DNA damage eventually resulting in tumor formation. Therefore, we studied resveratrol for its long term DNA protective and cancer chemopreventive potential in wild type and Ogg1; Myh double mutant mice in vivo. Almost all Ogg1; Myh double mutant control mice developed lymphomas or ovarian, GI-tract or lung tumors before they reached the age of 14 month. In the resveratrol group where animals received Resveratrol loaded hydrogel from weaning to death animals of different ages are still alive and survival curves are already significantly different. This suggests that long term administration of resveratrol is able to delay the occurrence of tumors in these mice if resveratrol uptake is frequent and regular and that moderate doses are sufficient.