A Derivative of Oleanolic Acid: Anti-Hepatocellular Carcinoma (HCC) Activity

描述(申请人提供)：肝细胞癌是世界上最常见的肿瘤之一，其发病率正在增加。目前，还没有专门控制肝细胞癌生长的化疗药物。值得注意的是，高水平的一氧化氮(NO)及其衍生的RNS和ROS对肝癌细胞具有细胞毒性。齐墩果酸(OA)被证明可以保护肝细胞免受炎症和其他毒物介导的肝损伤，这与调节某些CYP的活性有关。正常肝细胞高水平表达那些对OA敏感的和其他关键的药物代谢的细胞色素P450，而肝癌细胞只表达少量的对OA不敏感的细胞色素P450。肝癌细胞和正常肝细胞CYP表达的差异，再加上肝癌细胞的其他独特性质，如肝癌细胞中高水平的硫醇，可能导致它们对ZCIII9的生物代谢能力的显著差异，从而导致非供体的代谢产物的差异。事实上，我们的初步研究表明，NO释放衍生物ZCIII9在肝癌细胞中诱导高水平的亚硝酸盐和过氧化氢的产生，而在正常肝细胞中低水平的亚硝酸盐和过氧化氢的产生，并选择性地诱导肝癌细胞(HepG2和Hep3b)在体外以剂量和时间依赖的方式诱导凋亡。重要的是，ZCIII9治疗，而不是对照的OA，抑制了体内接种的肝癌的生长，但不损害小鼠的肝脏。因此，我们推测，ZCIII9治疗将在肝癌细胞中产生高水平的毒性RNS和ROS，导致对肝癌细胞的选择性细胞毒作用，这是由于ZCIII9在肝癌细胞中缺乏药物生物灭活的Cyps，减少/耗尽GSH，和/或内源性CYP的生物激活而导致的。在这项研究中，我们将重点考察不同剂量的ZCIII9对体内接种的肝癌生长的治疗作用，并确定ZCIII9抑制肝癌生长的机制(S)。总之，我们的数据可能为调节RNS和ROS介导的肝细胞毒性提供新的见解。我们的发现可能为设计针对肝细胞癌患者的特异性化疗药物提供依据。外行摘要：我们将集中研究一种合成化合物的抗肝癌活性。我们的发现可能为设计针对人类患者的人肝癌特异性化疗药物提供依据。

DESCRIPTION (provided by applicant): 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.