Cancer chemoprevention by dietary phytochemicals: In vitro and in vivo molecular mechanisms.

摘要

Epidemiological studies have suggested that both genetic and environmental factors contribute to the incidence of cancer in human. Dietary cancer chemopreventive agents could either block the initiation step or suppress both promotion and progression steps of cancer development. The involved mechanisms include the regulation of nuclear factor E2-related factor 2 (Nrf2)-mediated Phase II detoxification gene transcription and signaling pathways related to cell proliferation and apoptosis. Therefore, purpose of our studies is to further elucidate cancer chemopreventive mechanisms of dietary phytochemicals and the role of Nrf2 in their cancer protective function. Since mitogen-activated protein kinases (MAPKs) could regulate Nrf2/ARE signaling pathway in response to chemopreventive agent treatment, our first in vitro study showed that Nrf2 transactivation domain activity could be upregulated by both ERK and JNK pathways but negatively regulated by p38, and nuclear coactivator CBP might be involved in this regulation. Next, the cancer suppressing mechanism of sulforaphane in HT-29 cells was addressed by an in vitro study, in which sulforaphane could induce p53-independent G1 cell cycle arrest by induction of p21CIP1 and inhibition of cyclin D1. Using the ApcMin/+ mice colon cancer model, we further showed that dietary administration of sulforaphane (600ppm), dibenzoylmethane (1%), or in combination with half dose could inhibit both intestinal and colon tumorigenesis significantly; these effects were associated with the inhibition of arachidonic acid metabolism and regulation of biomarkers involved in cell growth and apoptosis. Cancer chemopreventive agents-regulated Nrf2-dependent genes were identified by comparing gene expression profiles of EGCG- and curcumin-treated wildtype and Nrf2 knockout mice. We found that in addition to Phase II genes, Nrf2 was also essential to regulate genes with a wide variety of function such as transport, cell growth and apoptosis, cell adhesion etc. Since many drug metabolism enzyme genes were identified as Nrf2-dependent genes, genetic knockout of Nrf2 in C57BL/6J mice significantly changed the pharmacokinetic characteristics of dibenzoylmethane in our last study, which was further supported by elucidating the dibenzoylmethane metabolic pathways. In summary, this dissertation improves our understanding of the molecular mechanisms of cancer chemoprevention by dietary phytochemicals and the contribution of Nrf2 in some of the processes.