Oncogenes as Molecular Targets for NaturalProduct Cancer Preventive and Therapeutic Agents

Although many natural products have been shown to have significant anticancer activities in preventive and therapeutic models in vitro and in vivo, including epidemiological studies, the underlying mechanisms of action remain unclear. This presentation will focus on the effects and molecular mechanisms of several natural products on oncogene expression and functions. The oncoprotein MDM 2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and -independent activities. We have identified several natural MDM 2 inhibitors such as curcumin, genistein, and ginsenosides, among others. For instance, curcumin, which has previously been shown to have anticancer activity, down-regulates MDM 2, independent of p53, which is critical to its anticancer effects in several cancer models. In a human prostate cancer cell line PC3 (p53 ^null ), curcumin reduced MDM 2 protein and mRNA in a dose- and time-dependent manner, and enhanced the expression of the tumor suppressor p21 ^Waf1/CIP1 . The inhibitory effects occur at the transcriptional level and appear to involve the PI3 kinase/mTOR/ETS2 pathway. Curcumin also induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM 2 overexpression and knockdown reduced these effects. When it was administered to tumor-bearing nude mice, curcumin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of MDM 2. We have also demonstrated that down-regulation of the MDM 2 oncogene is a novel mechanism of action that may be essential for its chemopreventive and chemotherapeutic effects of genistein and a novel ginsenoside 25CH3-PPD. These studies may provide a new avenue for mechanistic studies of natural product cancer preventive and therapeutic agents. Acknowledgements: The work was supported in part by NIH/NCI grants R01 CA112029 and R01 CA12121.