Original articles
Fangfang Wang, Sora Jin, Franklin Mayca Pozo, Danmei Tian, Xiyang Tang, Yi Dai, Xinsheng Yao, Jinshan Tang, Youwei Zhang. Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1339-1350

Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR
Fangfang Wanga,b, Sora Jinc, Franklin Mayca Pozoc, Danmei Tiana,b, Xiyang Tanga,b, Yi Daia,b, Xinsheng Yaoa,b, Jinshan Tanga,b, Youwei Zhangc
a. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China;
b. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drug Research, Jinan University, Guangzhou 510632, China;
c. Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Abstract:
DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.
Key words:    Chemical screen    Shikonin    DNA damage Response    ATM    ATR    ATRIP    Protein degradation    Chemo sensitizing   
Received: 2021-05-14     Revised: 2021-07-26
DOI: 10.1016/j.apsb.2021.08.025
Funds: This work was supported by Guangdong Basic and Applied Basic Research Foundation (2021A1515011244, China) to Jinshan Tang and the National 111 Project of China (No. B13038, China) to Xinsheng Yao.
Corresponding author: Xinsheng Yao,E-mai:tyaoxs@jnu.edu.cn;Jinshan Tang,E-mai:jstang0615@jnu.edu.cn;Youwei Zhang,E-mai:yxz169@case.edu     Email:tyaoxs@jnu.edu.cn;jstang0615@jnu.edu.cn;yxz169@case.edu
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Authors
Fangfang Wang
Sora Jin
Franklin Mayca Pozo
Danmei Tian
Xiyang Tang
Yi Dai
Xinsheng Yao
Jinshan Tang
Youwei Zhang

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