羧胺三唑抑制肿瘤细胞线粒体氧化磷酸化的作用机理及基于此作用的药效优化研究

Targeting cancer cell metabolism is a promising strategy against cancer. Pancreatic cancers are metabolically heterogeneous: cancer stem cells rely on mitochondrial respiration and have decreased glycolytic activity with respect to their more differentiated progeny. Our preliminary data have shown that the novel anticancer drug carboxyamidotriazole can greatly inhibit the oxidative phosphorylation in cancer cells and its anticancer effect can be enhanced by a glycolysis inhibitor. Based on these observations, this project firstly aims to further search the target(s) of carboxyamidotriazole in mitochondria and clarify its selectivity between cancer cells and normal cells. Secondly, the enhancement of the anticancer efficacy of carboxyamidotriazole will be investigated based on its effect on the mitochondrial respiration. The planned enhancement strategies includes: (1) the combination of carboxyamidotriazole and other energy metabolism interrupting drugs in more xenograft tumor models; (2) the combination of carboxyamidotriazole and gemcitabine to test whether the former can inhibit the viability of pancreatic cancer stem cells and prevent the gemcitabine resistance and cancer recurrence. The work will provide new evidences for the application of the oxidative phosphorylation inhibitors in cancer therapy and may supply a new effective strategy against pancreatic cancer.

针对能量代谢的抗肿瘤治疗策略在近年来受到广泛关注。在胰腺癌等恶性肿瘤中，肿瘤细胞的能量代谢具有异质性——大量分化肿瘤细胞主要进行糖酵解代谢，而肿瘤干细胞主要依赖线粒体氧化磷酸化产生能量。申请者研究初步发现，羧胺三唑对肿瘤细胞的线粒体氧化磷酸化有显著抑制作用，与糖酵解抑制剂合用的抗肿瘤作用显著增强。本项目计划一方面深入寻找羧胺三唑在线粒体中的关键靶点，并分析其在正常细胞和肿瘤细胞之间的选择性；另一方面利用羧胺三唑对氧化磷酸化的抑制作用，寻找合理配伍使其抗肿瘤疗效得到优化。预期方案一为在更多荷瘤模型上观察羧胺三唑与糖酵解抑制剂等其它能量代谢干扰药物合用的疗效；预期方案二为羧胺三唑与吉西他滨合用，对胰腺癌干细胞活力进行干预，尝试抑制胰腺癌的发生、复发和转移，改善吉西他滨耐药。本课题将为氧化磷酸化抑制剂在抗肿瘤治疗中的应用增加新的证据支持，并可能能够发展胰腺癌新的有效治疗策略。

胰腺癌、胶质母细胞瘤等类型的肿瘤预后极差，临床上急需新的治疗思路的补充。近年来，干扰线粒体代谢功能的药物显示出潜在的抗肿瘤作用。我们的前期工作表明，羧胺三唑具有较强的抗肿瘤作用和线粒体氧化呼吸抑制作用。在本项研究中，我们证实了羧胺三唑对线粒体呼吸链的抑制作用，探讨了这一作用对肿瘤增殖和自噬，以及肿瘤相关巨噬细胞表型的影响，分析了这一作用引起的细胞能量代谢重编程过程，在此基础上探索了羧胺三唑与其它代谢干扰药物组合的抗肿瘤作用。研究发现，羧胺三唑引起的肿瘤细胞和巨噬细胞代谢重编程作用十分显著，几种药物组合方案显示出增强的抗肿瘤疗效：1. 羧胺三唑与糖酵解抑制剂2-脱氧葡萄糖合用显著抑制吉西他滨停药后的胰腺癌生长；2. 羧胺三唑与谷氨酰胺酶抑制剂CB839合用显著抑制胶质母细胞瘤的增殖；3. 羧胺三唑与吲哚-2,3双加氧酶抑制剂1-MT合用显著延长多种肿瘤模型动物的生存期；4. 羧胺三唑及其组合方案显著下调肿瘤相关巨噬细胞中促癌介质的表达。本项研究阐释了羧胺三唑的抗肿瘤作用机理，为干扰能量物质代谢的抗肿瘤药物研发思路提供了新的证据，以羧胺三唑等线粒体代谢调控药物为基础的药物组合可能能够成为胰腺癌、胶质瘤等预后极差的恶性肿瘤的辅助治疗策略。