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Tumor Biology

, Volume 37, Issue 11, pp 14745–14755 | Cite as

Geldanamycin, an inhibitor of Hsp90, increases paclitaxel-mediated toxicity in ovarian cancer cells through sustained activation of the p38/H2AX axis

  • Qingqing Mo
  • Yu Zhang
  • Xin Jin
  • Yue Gao
  • Yuan Wu
  • Xing Hao
  • Qinglei Gao
  • Pingbo Chen
Original Article

Abstract

Paclitaxel is a mitotic inhibitor used in ovarian cancer chemotherapy. Unfortunately, due to the rapid genetic and epigenetic changes in adaptation to stress induced by anticancer drugs, cancer cells are often able to become resistant to single or multiple anticancer agents. However, it remains largely unknown how paclitaxel resistance happens. In this study, we generated a cell line of acquired resistance to paclitaxel therapy, A2780T, which is cross-resistant to other antimitotic drugs, such as PLK1 inhibitor or AURKA inhibitor. Immunoblotting revealed significant alterations in cell-cycle-related and apoptotic-related proteins involved in key signaling pathways. In particular, phosphorylation of p38, which activates H2AX, was significantly decreased in A2780T cells compared to the parental A2780 cells. Geldanamycin (GA), an inhibitor of Hsp90, sustained activation of the p38/H2AX axis, and A2780T cells were shown to be more sensitive to GA compared to A2780 cells. Furthermore, treatment of A2780 and A2780T cells with GA significantly enhanced sensitivity to paclitaxel. Meanwhile, GA cooperated with paclitaxel to suppress tumor growth in a mouse ovarian cancer xenograft model. In conclusion, GA may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by inactivation of p38/H2AX axis.

Keywords

Geldanamycin Hsp90 inhibitor Paclitaxel Ovarian cancer p38/H2AX axis 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 81072135, 81372801, 81572570).

Compliance with ethical standards

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution.

Conflicts of interest

None.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Cancer Biology Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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