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

描述（由申请人提供）：HCC是全球最常见的肿瘤之一，其发病率正在增加。目前，没有化疗可用于特异性控制HCC生长。值得注意的是，高水平的一氧化氮（NO）、其衍生的RNS和ROS对HCC细胞可能具有细胞毒性。油酸（OA）已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，这与调节某些酶的活性有关。正常肝细胞表达高水平的OA敏感性和其他关键药物代谢CYP，而HCC细胞仅表达低水平的少数OA不敏感性CYP。HCC细胞和正常肝细胞之间ZCIII表达的差异，以及HCC细胞的其他独特性质，例如HCC细胞中高水平的硫醇，可能导致它们生物代谢ZCIII 9的能力的显著差异，导致NO供体的差异代谢产物。事实上，我们的初步研究表明，ZCIII 9，一个NO释放衍生物的OA，诱导高水平的亚硝酸盐和H2 O2的生产在肝癌细胞中，但在正常的人肝细胞中的低水平，并选择性诱导肝癌细胞（HepG 2和Hep 3b）凋亡在体外的剂量和时间依赖性的方式。重要的是，用ZCIII 9处理而不是对照OA抑制了体内接种的HCC生长，但不损害小鼠肝脏。因此，我们假设用ZCIII 9治疗将在HCC细胞中产生高水平的毒性RNS和ROS，导致对HCC细胞的选择性细胞毒性，这是由HCC细胞中缺乏药物生物灭活CYP导致的ZCIII 9的生物灭活缺陷介导的，减少/耗尽GSH和/或内源性GSH的生物活化。在该提议中，我们将集中于检查用不同剂量的ZCIII 9治疗对体内接种的HCC生长的治疗效果，并确定ZCIII 9抑制HCC生长的治疗效果的潜在机制。总之，我们的数据可能会提供新的见解RNS和ROS介导的细胞毒性对肝细胞的调节。我们的研究结果可能为肝癌患者的肝癌特异性化疗方案的设计提供依据。外行摘要：我们将集中研究一种合成化合物的抗肝癌活性。我们的研究结果可能为人类肝癌特异性化疗的设计提供依据。

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.