Early responses of the STAT3 pathway to platinum drugs are associated with cisplatin resistance in epithelial ovarian cancer

W.J Sheng,J.H Zheng,H Jiang,D.L Wu

doi:10.1590/1414-431x20133003

Abstract

Cisplatin resistance remains one of the major obstacles when treating epithelial ovarian cancer. Because oxaliplatin and nedaplatin are effective against cisplatin-resistant ovarian cancer in clinical trials and signal transducer and activator of transcription 3 (STAT3) is associated with cisplatin resistance, we investigated whether overcoming cisplatin resistance by oxaliplatin and nedaplatin was associated with the STAT3 pathway in ovarian cancer. Alamar blue, clonogenic, and wound healing assays, and Western blot analysis were used to compare the effects of platinum drugs in SKOV-3 cells. At an equitoxic dose, oxaliplatin and nedaplatin exhibited similar inhibitory effects on colony-forming ability and greater inhibition on cell motility than cisplatin in ovarian cancer. Early in the time course of drug administration, cisplatin increased the expression of pSTAT3 (Tyr705), STAT3α, VEGF, survivin, and Bcl-XL, while oxaliplatin and nedaplatin exhibited the opposite effects, and upregulated pSTAT3 (Ser727) and STAT3β. The STAT3 pathway responded early to platinum drugs associated with cisplatin resistance in epithelial ovarian cancer and provided a rationale for new therapeutic strategies to reverse cisplatin resistance.

Highlights

IntroductionEpithelial ovarian cancer accounts for approximately 90% of ovarian malignancies and is often discovered at an advanced stage, with a 5-year survival rate of less than 20% [1]
Since oxaliplatin and nedaplatin have been effective against cisplatin-resistant ovarian cancer in clinical trials, and targeting signal transducer and activator of transcription 3 (STAT3) may reverse drug resistance, we investigated whether the effects of platinum agents on the STAT3 pathway were associated with cisplatin resistance
STAT3-targeted therapies could potentiate the effect of cisplatin [8,12], some researchers found that pretreatment of platinum-resistant cells with AG490 resulted in no significant increase in sensitivity to cisplatin [18]

Summary

Introduction

Epithelial ovarian cancer accounts for approximately 90% of ovarian malignancies and is often discovered at an advanced stage, with a 5-year survival rate of less than 20% [1]. Nedaplatin, a second-generation platinum drug, has a higher water solubility than cisplatin and causes fewer side effects [3]. Oxaliplatin, a third-generation platinum compound, displays wide antitumor activity against cancers restricted to the peritoneal cavity and showed partial cross-resistance to cisplatin in preclinical studies [4]. Both nedaplatin and oxaliplatin are effective in heavily pretreated ovarian cancer patients who are nonresponsive to cisplatin, with manageable toxicity [4,5,6]. The mechanism underlying their reversal of cisplatin resistance remains largely unknown. Signal transducer and activator of transcription 3 (STAT3) overexpression has been reported positively associated with cisplatin resistance [8]

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