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

Content Provider	Springer Nature Link
Author	Mo, Qingqing Zhang, Yu Jin, Xin Gao, Yue Wu, Yuan Hao, Xing Gao, Qinglei Chen, Pingbo
Copyright Year	2016
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.
Starting Page	14745
Ending Page	14755
Page Count	11
File Format	PDF
ISSN	10104283
Journal	Tumor Biology
Volume Number	37
Issue Number	11
e-ISSN	14230380
Language	English
Publisher	Springer Netherlands
Publisher Date	2016-09-15
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	Geldanamycin Hsp90 inhibitor Paclitaxel Ovarian cancer p38/H2AX axis Cancer Research
Content Type	Text
Resource Type	Article
Subject	Medicine Cancer Research

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