HCC is one of the most frequent neoplasms worldwide and its incidence is increasing. Currently, there is no chemotherapy available to specifically control HCC growth. Notably, high levels of nitric oxide (NO), its derived RNS and ROS, can be cytotoxic for HCC cells. Oleanolic acid (OA) has been shown to protect the liver cells from inflammation and other toxicant-mediated liver injury, which is associated with modulating some CYP's activities. While normal liver cells express high levels of those OA-sensitive and other crucial drug-metabolic CYPs, HCC cells only express low levels of a few OA-insensitive CYPs. The difference in CYP expression between HCC cells and normal liver cells, together with other unique properties of HCC cells, such as high levels of thiols in HCC cells, may result in a significant difference in their abilities to bio-metabolize ZCIII9, leading to differential metabolic products of NO-donors. Indeed, our preliminary studies have shown that ZCIII9, a NO-releasing derivative of OA, induces high levels of nitrite and H2O2 production in HCC cells, but low levels of them in normal human liver cells, and selectively induces HCC cell (HepG2 and Hep3b) apoptosis in vitro in a dose- and time-dependent manner. Importantly, treatment with ZCIII9, but not control OA, inhibits inoculated HCC growth in vivo, but did not damage mouse liver. Hence, we hypothesize that treatment with ZCIII9 will produce high levels of toxic RNS and ROS in HCC cells, leading to selective cytotoxicity on HCC cells, which is mediated by deficient bioinactivation of ZCIII9 due to the lack of drug-bioinactivative CYPs in HCC cells, reducing/depleting GSH, and/or endogenous CYP's bioactivation. In this proposal, we will center on examining the therapeutic effects of treatment with different dosages of ZCIII9 on the growth of inoculated HCC in vivo and to determine the mechanism(s) underlying the therapeutic effects of ZCIII9 on inhibition of HCC growth. Together, our data may provide new insights into the regulation of RNS- and ROS-mediated cytotoxicity on liver cells. Our findings may provide a basis for the design of HCC-specific chemotherapies for HCC patients. Layperson's abstract: We will center on examining the anti-liver cancer activity of a synthetic chemical compound. Our findings may provide a basis for the design of human liver cancer-specific chemotherapies for human patients. ? ? ? ?
| Chen, Li; Zhang, Yihua; Kong, Xiangwen et al. (2008) Design, synthesis, and antihepatocellular carcinoma activity of nitric oxide releasing derivatives of oleanolic acid. J Med Chem 51:4834-8 |
| Chen, Li; Zhang, Yihua; Kong, Xiangwen et al. (2007) Synthesis and biological evaluation of nitric oxide-releasing derivatives of oleanolic acid as inhibitors of HepG2 cell apoptosis. Bioorg Med Chem Lett 17:2979-82 |
