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

齐墩果酸衍生物：抗肝细胞癌 (HCC) 活性

• 批准号: 7268008
• 负责人: JIDE TIAN
• 金额: $ 14.25万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268008
• 关键词: Apoptosis; Cells; Chemicals; Data; Dose; Growth; Hepatocyte; Human; Hydrogen Peroxide; In Vitro; Incidence; Inflammation; Injury; Liver; Malignant neoplasm of liver; Mediating; Metabolic; Mus; Neoplasms; Nitric Oxide; Nitric Oxide Donors; Nitrites; Normal Cell; Oleanolic Acid; Patients; Pharmaceutical Preparations; Primary carcinoma of the liver cells; Production; Property; Regulation; Sulfhydryl Compounds; Therapeutic Effect; Time; abstracting; base; chemotherapy; cytotoxic; cytotoxicity; design; dosage; in vivo; insight; toxicant

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（由申请人提供）：HCC 是世界上最常见的肿瘤之一，其发病率正在增加。目前，没有可用于专门控制 HCC 生长的化疗方法。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，这与调节某些 CYP 的活性有关。虽然正常肝细胞表达高水平的 OA 敏感型和其他关键药物代谢 CYP，但 HCC 细胞仅表达低水平的少数 OA 不敏感型 CYP。 HCC细胞和正常肝细胞之间CYP表达的差异，加上HCC细胞的其他独特特性，例如HCC细胞中高水平的硫醇，可能导致它们生物代谢ZCIII9的能力存在显着差异，从而导致NO供体的代谢产物存在差异。事实上，我们的初步研究表明，ZCIII9（一种释放 NO 的 OA 衍生物）可诱导 HCC 细胞产生高水平的亚硝酸盐和 H2O2，但在正常人肝细胞中产生低水平的亚硝酸盐和 H2O2，并以剂量​​和时间依赖性方式在体外选择性诱导 HCC 细胞（HepG2 和 Hep3b）凋亡。重要的是，用 ZCIII9（而非对照 OA）治疗可抑制体内接种的 HCC 生长，但不会损伤小鼠肝脏。因此，我们假设用 ZCIII9 治疗将在 HCC 细胞中产生高水平的有毒 RNS 和 ROS，导致对 HCC 细胞产生选择性细胞毒性，这是由于 HCC 细胞中缺乏药物生物灭活 CYP、减少/耗尽 GSH 和/或内源 CYP 生物活化而导致 ZCIII9 生物灭活缺陷介导的。在本提案中，我们将集中研究不同剂量的ZCIII9治疗对体内接种的HCC生长的治疗效果，并确定ZCIII9抑制HCC生长的治疗作用的机制。总之，我们的数据可能为 RNS 和 ROS 介导的肝细胞细胞毒性的调节提供新的见解。我们的研究结果可能为 HCC 患者设计 HCC 特异性化疗提供基础。外行摘要：我们将集中研究合成化合物的抗肝癌活性。我们的研究结果可能为人类患者设计人类肝癌特异性化疗药物提供基础。