Oxidative DNA double strand breaks and autophagy in the antitumor effect of sterically hindered platinum(II) complexes in NSCLCs
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Feihong Chen1, Xinyi Wang1, Xiufeng Jin1, Jian Zhao1, Shaohua Gou1
1Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China
Shaohua Gou, email: email@example.com
Keywords: platinum(II) complexes, N1, N2-diisobutyl moiety, ROS, double strand breaks, MDC1/aprataxin
Received: December 20, 2016 Accepted: February 23, 2017 Published: March 06, 2017
A series of novel platinum(II) complexes with (1R,2R)-N1,N2-diisobutyl-1,2-diaminocyclohexane as a carrier ligand, while N1,N2-diisobutyl moiety serving as steric hindrance were designed, synthesized and characterized. The in vitro biological assays demonstrated that complex 3 had increased cytotoxicity against lung cancer cells, especially non-small-cell lung cancer (NSCLC) compared to its mono-substituted complex 3a, indicating that the sterically hindered alkyl moieties have significant influences on its antitumor property. However, the mechanism still remains unclear. The further studies revealed that complex 3 could induce ROS overproduction, severe DNA double strands breaks and inhibit the activation of DNA damage repair proteins within nucleus, leading to cell-cycle arrest and cell death. Moreover, complex 3 could induce autophagy via the accumulation of autophagic vacuoles and alterations of autophagic protein expression. Interestingly, the ROS scavengers, N-acetyl-cysteine (NAC) could reverse complex 3-induced DNA double strands breaks and autophagic responses more significantly compared to complex 3a. The results demonstrated that the ROS generation plays an important role in the DNA double strands breaks and autophagic responses in the antitumor effect of complex 3 with N1,N2-diisobutyl moiety. Our study offered a novel therapeutic strategy and put new insights into the anticancer research of the complexes with N1,N2-diisobutyl moiety served as steric hindrance.
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