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Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes

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Abstract

Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH3)2Cl]2L1}(NO3)2 (1) and {[cis-Pt(NH3)2Cl]2L2}(NO3)2 (2) (L1 = α,α′-diamino-p-xylene, L2 = 4,4′-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.

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Acknowledgments

We acknowledge the financial support from the National Natural Science Foundation of China (Grants 20631020, 90713001, 20721002, and 30870554) and the Natural Science Foundation of Jiangsu Province (Grant BK2008015).

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Authors and Affiliations

  1. State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, People’s Republic of China

    Miaoxin Lin, Jianhui Zhu, Damin Fan, Yangmiao Zhang & Zijian Guo

  2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, People’s Republic of China

    Xiaoyong Wang & Junfeng Zhang

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  1. Miaoxin Lin
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  2. Xiaoyong Wang
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  3. Jianhui Zhu
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  7. Zijian Guo
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Correspondence to Xiaoyong Wang or Zijian Guo.

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Lin, M., Wang, X., Zhu, J. et al. Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes. Apoptosis 16, 288–300 (2011). https://doi.org/10.1007/s10495-010-0562-0

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