Anti-malarial atovaquone exhibits anti-tumor effects by inducing DNA damage in hepatocellular carcinoma

American Journal of Cancer Research

Xiaoge Gao¹  Qian Liu²  Chao Wang³  Xiangye Liu⁴  Wenhua Shan⁵ 

[1] Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, P. R. China;Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, P. R. China;Jiangsu Center for The Collaboration and Innovation of Cancer Biotherapy, 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;School of Stomatology, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, P. R. China

关键词: Hepatocellular carcinoma;    atovaquone;    cell cycle arrest;    apoptosis;    DNA double-strand breaks;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

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 in vivo, 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.

【 授权许可】

CC BY-NC