Qiu Mingning, Ke Longzhi, Zhang Sai, Zeng Xin, Fang Zesong, Liu Jianjun
Laboratory of Urology, Guangdong Medical University, Zhanjiang, 524001, China.
Cancer Chemother Pharmacol. 2017 Aug;80(2):275-286. doi: 10.1007/s00280-017-3359-9. Epub 2017 Jun 12.
Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells.
The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species.
We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production.
JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.
多柔比星是一种在多种化疗方案中高效且广泛使用的蒽环类抗生素，但其心脏毒性限制了其应用。本研究旨在探讨一氧化氮供体前药JS-K对肾癌细胞增殖和凋亡的影响以及对多柔比星诱导的心肌细胞毒性的影响，并探索肾癌细胞中可能的p53相关机制。
通过检测细胞增殖、细胞毒性、细胞死亡和凋亡以及凋亡相关蛋白的表达，研究JS-K对多柔比星在肾癌细胞中抗癌活性的影响。使用p53抑制剂Pifithrin-α和p53激活剂III确定p53对JS-K与多柔比星联合作用的影响。此外，通过测量细胞生长、细胞死亡和凋亡、凋亡相关蛋白的表达以及细胞内活性氧，研究JS-K对H9c2(2-1)心肌细胞中多柔比星心脏毒性的影响。
我们证明JS-K可增强多柔比星诱导的肾癌细胞生长抑制和凋亡，并可增加参与凋亡的蛋白表达。此外，Pifithrin-α可逆转JS-K对多柔比星诱导的肾癌细胞凋亡的促进作用；相反，p53激活剂III可加剧JS-K对多柔比星诱导的肾癌细胞凋亡的促进作用。此外，JS-K可保护H9c2(2-1)心肌细胞免受多柔比星诱导的毒性，并减少多柔比星诱导的活性氧产生。
JS-K通过上调p53表达增强多柔比星在肾癌细胞中的抗癌活性，并通过降低氧化应激预防多柔比星的心肌细胞毒性。
