Gao Xiaoge, Liu Xiangye, Shan Wenhua, Liu Qian, Wang Chao, Zheng Jiwei, Yao Hong, Tang Renxian, Zheng Junnian
Cancer Institute, Xuzhou Medical University Xuzhou 221002, Jiangsu Province, P. R. China.
Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University Xuzhou 221004, Jiangsu Province, P. R. China.
Am J Cancer Res. 2018 Sep 1;8(9):1697-1711. eCollection 2018.
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is the third most frequent cause of cancer-related deaths worldwide. The development of safe new anti-tumor agents has become increasingly important due to the steady rise in drug-resistant tumors. After assessing the efficacy of several candidate compounds that could inhibit hepatocellular carcinoma, we focused on atovaquone, an FDA-approved anti-malarial drug. In the present study, we found that atovaquone significantly inhibited hepatoma cell proliferation via S phase cell cycle arrest and both extrinsic and intrinsic apoptotic pathway induction associated with upregulation of p53 and p21. Molecular investigations demonstrated that atovaquone inhibits hepatoma cell proliferation by inducing double-stranded DNA breaks, leading to sustained activation of ataxia-telangiectasia mutated (ATM) and its downstream molecules such as cell cycle checkpoint kinase-2 (CHK2) and H2AX. In addition, we found that atovaquone also induced apoptosis, inhibited both cell proliferation and angiogenesis , and prolonged the survival time of tumor-bearing mice, without any obvious side effects. In conclusion, our data indicate that atovaquone is a safe and effective candidate drug that could be rapidly repurposed for HCC treatment.
肝细胞癌（HCC）是原发性肝癌最常见的类型，也是全球癌症相关死亡的第三大常见原因。由于耐药肿瘤的稳步增加，开发安全的新型抗肿瘤药物变得越来越重要。在评估了几种可抑制肝细胞癌的候选化合物的疗效后，我们将重点放在了阿托伐醌上，这是一种经美国食品药品监督管理局（FDA）批准的抗疟药物。在本研究中，我们发现阿托伐醌通过使细胞周期停滞于S期以及诱导与p53和p21上调相关的外源性和内源性凋亡途径，显著抑制肝癌细胞增殖。分子研究表明，阿托伐醌通过诱导双链DNA断裂来抑制肝癌细胞增殖，从而导致共济失调毛细血管扩张症突变基因（ATM）及其下游分子如细胞周期检查点激酶2（CHK2）和H2AX的持续激活。此外，我们发现阿托伐醌还能诱导凋亡、抑制细胞增殖和血管生成，并延长荷瘤小鼠的生存时间，且无任何明显副作用。总之，我们的数据表明阿托伐醌是一种安全有效的候选药物，可迅速用于肝癌治疗的重新定位。
