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Hypoxia-induced resistance to cisplatin-mediated apoptosis in osteosarcoma cells is reversed by gambogic acid independently of HIF-1α

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Abstract

In vitro evidence of hypoxia-induced resistance to cisplatin (CDDP)-mediated apoptosis exists in human osteosarcoma (OS). Gambogic acid (GA) is a promising chemotherapeutic compound that could increase the chemotherapeutic effectiveness of CDDP in human OS cells by inducing cell cycle arrest and promoting apoptosis. This study examined whether GA could overcome OS cell resistance to CDDP. Hypoxia significantly reduced levels of CDDP-induced apoptosis in the OS cell lines MG63 and HOS. However, combined treatment with GA and CDDP revealed a strong synergistic action between these drugs, and higher protein levels of the apoptosis-related factor Fas, cleaved caspase-8 and cleaved caspase-3 and lower expression of hypoxia-inducible factor (HIF)-1α are detected in both cell lines. Meanwhile, drug resistance was not reversed by exposure to the HIF-1α inhibitor 2-methoxyestradiol. These findings strongly suggest that hypoxia-induced resistance to CDDP is reversed by GA in OS cells independently of HIF-1α. Furthermore, in vivo studies using xenograft mouse models revealed that combination therapy with CDDP and GA exerted increased antitumor effects by inducing apoptosis. Taken together, our results demonstrate that GA may be a new potent therapeutic agent useful for targeting human OS cells.

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Abbreviations

GA:

Gambogic acid

CDDP:

Cisplatin

2ME2:

2-Methoxyestradiol

OS:

Osteosarcoma

HIF-1α:

Hypoxia-inducible factor 1a

CCK-8:

Cell counting kit-8

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Acknowledgments

This study was supported by Grants from the National Natural Science Foundation of China (No. 81441081).

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    Authors and Affiliations

    1. Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China

      Wei Zhao, Shi-Qi Xia, Jin-Peng Zhuang, Zhi-Peng Zhang, Chang-Cheng You, Jing-Long Yan & Gong-Ping Xu

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    1. Wei Zhao
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    2. Shi-Qi Xia
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    Correspondence to Jing-Long Yan or Gong-Ping Xu.

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    Zhao Wei and Xia Shi-Qi have contributed equally to this work.

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    Zhao, W., Xia, SQ., Zhuang, JP. et al. Hypoxia-induced resistance to cisplatin-mediated apoptosis in osteosarcoma cells is reversed by gambogic acid independently of HIF-1α. Mol Cell Biochem 420, 1–8 (2016). https://doi.org/10.1007/s11010-016-2759-1

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    • DOI: https://doi.org/10.1007/s11010-016-2759-1

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