title: Reversing drug resistance of cisplatin by hsp90 inhibitors in human ovarian cancer cells.
abstract: OBJECTIVE
  To investigate the mechanisms for reversing drug resistance of cisplatin (DDP) by Hsp90 inhibitors (geldanamycin (GA), 17-AAG, 17-DMAG) in human ovarian cancer.
  
  
  METHODS
  Cell proliferation rate in DDP resistant human ovarian cancer cell line SKOV3/DDP and its parent cell line SKOV3 after treatment with Hsp90 inhibitors and/or DDP were tested by MTT assay, and the reversing fold (RF) of DDP by Hsp90 inhibitors was calculated. Cell cycle and cell apoptosis status after treatment were analyzed by flow cytometry. The expression of multiple drug resistance related genes was analyzed by RT-PCR and Western-blot.
  
  
  RESULTS
  All three tested Hsp90 inhibitors synergistically inhibited the cell proliferation of SKOV3 with DDP and enhanced the sensitivity of SKOV3/DDP cells to DDP. The RF of DDP by Hsp90 inhibitors were all more than two fold. GA caused cell cycle arrest in G2/M phasein SKOV3 cells. 17-AAG increased cell apoptosis but did not change cell cycle in SKOV3/DDP cells. The mRNA and protein expression levels of various drug resistant related genes including LRP, GST-π, p53, bcl-2, survivin, ERCC1, XRCC1, BRCA1 and BRCA2 were more dramatically altered by Hsp90 inhibitors and DDP in combination compared to Hsp90 inhibitors or DDP treatment alone.
  
  
  CONCLUSIONS
  Exposure of SKOV3/DDP cells to Hsp90 inhibitors and DDP in combination results in synergistic cytotoxic and pro-apoptotic effects. Hsp90 inhibitors reverse the drug resistance of SKOV3/DDP cells to DDP by modifying the expression of multiple drug resistance related genes.
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Pingfang
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Department of Gynecology and Obstetrics, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Qin
authors.affiliation: Research Center, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Hebei General Hospital Shijiazhuang 050000, China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Research Center, Fourth Houspital of Hebei Medical University Shijiazhuang 050011, China.
authors.forename: Baoen
authors.initials: B
authors.lastname: Shan
keywords: Hsp90 inhibitors; Ovarian cancer; cisplatin; heat shock protein 90; resistance genes