A Derivative of Oleanolic Acid: Anti-HCC Activity

齐墩果酸衍生物：抗 HCC 活性

• 批准号: 7147823
• 负责人: JIDE TIAN
• 金额: $ 14.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147823
• 关键词: chemotherapy; human; liver cells

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.

描述（申请人提供）：HCC是世界范围内最常见的肿瘤之一，其发病率呈上升趋势。目前，还没有化疗可用于特异性控制HCC的生长。值得注意的是，高水平的一氧化氮（NO）及其衍生的RNS和ROS可能对HCC细胞具有细胞毒性。齐墩果酸（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，这与调节一些CYP的活性有关。正常肝细胞表达高水平的oa敏感和其他关键的药物代谢CYPs， HCC细胞仅表达低水平的少数oa不敏感CYPs。HCC细胞与正常肝细胞之间CYP表达的差异，加上HCC细胞的其他独特性质，如HCC细胞中硫醇含量高，可能导致它们对ZCIII9的生物代谢能力存在显著差异，从而导致no供体代谢产物的差异。事实上，我们的初步研究表明，OA的no释放衍生物ZCIII9在HCC细胞中诱导高水平的亚硝酸盐和H2O2产生，而在正常人肝细胞中诱导低水平的亚硝酸盐和H2O2产生，并在体外以剂量和时间依赖性方式选择性诱导HCC细胞（HepG2和Hep3b）凋亡。重要的是，用ZCIII9治疗，但不控制OA，在体内抑制接种的HCC生长，但不损害小鼠肝脏。因此，我们假设用ZCIII9治疗会在HCC细胞中产生高水平的毒性RNS和ROS，导致肝癌细胞选择性细胞毒性，这是由HCC细胞中缺乏药物生物失活的CYPs导致ZCIII9生物失活不足、GSH减少/消耗和/或内源性CYP生物活化介导的。在本课题中，我们将重点研究不同剂量ZCIII9对体内接种的HCC生长的治疗作用，并确定ZCIII9抑制HCC生长的治疗作用机制。总之，我们的数据可能为RNS-和ros介导的肝细胞毒性调控提供新的见解。我们的发现可能为HCC患者设计HCC特异性化疗提供基础。外行人摘要：我们将集中研究一种合成化合物的抗肝癌活性。我们的发现可能为人类肝癌患者特异性化疗方案的设计提供依据。