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A novel oxaliplatin derivative, Ht-2, triggers mitochondrion-dependent apoptosis in human colon cancer cells

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Abstract

Ht-2 is a novel oxaliplatin derivative previously identified in a compound screen performed by our laboratory. In the present study, we evaluated the antitumor effects of Ht-2 and investigated its underlying mechanism of action. Ht-2 exhibited anti-tumor activity and demonstrated low cytotoxicity in normal cells in vitro. The IC50 of Ht-2 was 2–10-fold lower than oxaliplatin in all of the cancer cell lines tested except MCF-7 cells, whereas, the value was threefold higher than cisplatin or oxaliplatin in normal HUVEC cells. Further studies indicated that Ht-2 caused S-phase arrest and led to apoptosis in HCT-116 cells through the activation of the caspase cascade. Moreover, Ht-2 treatment contributed to increased mitochondrial permeability by altering the Bax/Bcl-2 ratio and consequently induced mitochondrial dysfunction, mitochondrial membrane potential depletion, reactive oxygen species (ROS) elevation and cytochrome C release in HCT-116 cells. The cellular antioxidative superoxide dismutase 1 protein was also downregulated. We demonstrated that the cytotoxicity was almost completely recovered by antioxidant treatment, indicating a crucial role of ROS for Ht-2-induced apoptosis. Collectively, our data suggest that Ht-2 can target tumor cells by inducing mitochondrion-dependent apoptosis.

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (No. 21272041), the National Key High-Tech Innovation Project for the R&D of Novel Drugs (No. 2013ZX09402102-001-006) and Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

    Yingying Xing, Weiwei Bao, Xiaobo Fan, Kunmei Liu, Xiaokang Li & Tao Xi

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  1. Yingying Xing
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  2. Weiwei Bao
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  3. Xiaobo Fan
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  4. Kunmei Liu
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  5. Xiaokang Li
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  6. Tao Xi
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Corresponding author

Correspondence to Tao Xi.

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10495_2014_1044_MOESM1_ESM.tif

Fig. S1 Chemical structures of cisplatin, oxaliplatin and Ht-2. (A) The chemical formula of cisplatin (Cl2H6N2Pt, WM = 300.05) B) The chemical formula of oxaliplatin (C8H12N2O4Pt, MW = 395.27). (C) The chemical formula of ht-2 (C13H19Cl2FN2Pt, WM = 488.05). (D) Binding specificity of Ht-2 with DNA. pcDNAs supplemented with different concentrations of Ht-2 were incubated for 24 h and then applied to 4 % agarose gel for electrophoresis (TIFF 8795 kb)

10495_2014_1044_MOESM2_ESM.tif

Fig. S2 Ht-2 shows less cytotoxicity against human umbilical vein endothelial cells (HUVEC) compared with cisplatin and oxaliplatin. Cell viability was assessed the same as Fig.S3A. Each data was obtained from at least three parallel experiment and expressed as mean ± SD. (*P < 0.05, **P < 0.01) (TIFF 165 kb)

10495_2014_1044_MOESM3_ESM.tif

Fig. S3 Ht-2 inhibits viability of HCT-116 cells in a time and dose dependent manner. (A) Inhibitory effects of Ht-2, cisplatin and oxaliplatin against HCT-116 cells. Cells were cultured overnight before treated with different dosage of ht-2, cisplatin and oxaliplatin. After incubated for 48 h, cell was measured for viability using CCK-8 Kit. B)ht-2 inhibits cell viability in a time- and dose-dependent manner. Cells were treated with serial dosages of ht-2 for 24, 48 or 72 h before sent to the microplate reader. Each value was expressed as mean ± SD. (*P < 0.05, **P < 0.01) (TIFF 19097 kb)

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Xing, Y., Bao, W., Fan, X. et al. A novel oxaliplatin derivative, Ht-2, triggers mitochondrion-dependent apoptosis in human colon cancer cells. Apoptosis 20, 83–91 (2015). https://doi.org/10.1007/s10495-014-1044-6

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