Autophagy inhibition enhances apoptosis triggered by BO-1051, an N-mustard derivative, and involves the ATM signaling pathway

Li Hsin Chen, Che Chuan Loong, Tsann Long Su, Yi Jang Lee, Pei Ming Chu, Ming Long Tsai, Ping Hsin Tsai, Pang Hsien Tu, Chin Wen Chi, Hsin Chen Lee, Shih Hwa Chiou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


In a previous study, BO-1051, an N-mustard linked with a DNA-affinic molecule, was shown to target various types of cancer cell lines. In the present study, we aimed to investigate the cytotoxicity, as well as the underlying mechanism, of BO-1051. We found that BO-1051 simultaneously induced apoptosis and autophagy in hepatocellular carcinoma cell lines. DNA double strand breaks induced by BO-1051 activated the ATM signaling pathway and subsequently resulted in caspase-dependent apoptosis. When autophagy was inhibited in its early or late stages, apoptosis was significantly enhanced. This result indicated autophagy as a cytoprotective effect against BO-1051-induced cell death. We further inhibited ATM activation using an ATM kinase inhibitor or ATM-specific siRNA and found that while apoptosis was blocked, autophagy also diminished in response to BO-1051. We not only determined a signaling pathway induced by BO-1051 but also clarified the linkage between DNA damage-induced apoptosis and autophagy. We also showed that BO-1051-induced autophagy acts as a cytoprotective reaction and downstream target of the ATM-signaling pathway. This research revealed autophagy as a universal cytoprotective response against DNA damage-inducing chemotherapeutic agents, including BO-1051, cisplatin, and doxorubicin, in hepatocellular carcinoma cell lines. Autophagy contributes to the remarkable drug resistance ability of liver cancer.

Original languageEnglish
Pages (from-to)594-605
Number of pages12
JournalBiochemical Pharmacology
Issue number5
StatePublished - 1 Mar 2011


  • Apoptosis
  • ATM
  • Autophagy
  • Hepatoma
  • N-mustard


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