Early Responses Of STAT3 Pathway To Platinum Drugs Associate With Cisplatin-resistance In Epithelial Ovarian Cancer

Introduction: Cisplatin resistance remains one of the major obstacles in treating epithelial ovarian cancer. Signal transducer and activator of transcription 3(STAT3) and pSTAT3 are overexpressed in cisplatin-resistant and recurrent ovarian cancer patients in clinical tumor specimens. Since oxaliplatin and nedaplatin are effective against cisplatin-resistant ovarian cancer in clinical trials, their mechanisms of anticancer effects might be different from those of cisplatin. Therefore, we compared effects of platinum drugs(cisplatin, oxaliplatin, nedaplatin) on ovarian cancer cells to explore the possible mechanisms of overcoming cisplatin resistance by oxaliplatin and nedaplatin.Methods: In this experiment, we used human ovarian cancer cell line SKOV-3, which expressed high levels of pSTAT3, to study the effects of platinum drugs on epithelial ovarian cancer. We used Alamar Blue assay to compare the cytotoxic effects of platinum drugs(cisplatin, oxaliplatin, nedaplatin) in SKOV-3 cells, in order to find out the equitoxic doses. Clonogenic assay was used to detect the sensitivity of equitoxic doses of platinum drugs and further confirm the effects of the drugs. The effects of platinum drugs on cell migration were performed by wound healing assay. Western blot analysis was used to explore and compare the effects of platinum drugs on STAT3 pathway and its downstream protein.Results: While cisplatin(1μg/ml) inhibited cell proliferation by approximately 50% by 48 h, oxaliplatin(8μg/ml) and nedaplatin(8μg/ml) demonstrated similar effects. Platinum agents of equitoxic dose exhibited similar inhibitory effect on colony-forming ability, showing less than 10% survival compared with the untreated control groups. Both 8μg/ml oxaliplatin and 8μg/ml nedaplatin, inhibited approximately 10% of the SKOV-3 cell migration, while cisplatin showed almost no inhibitory effect on cell migration. We observed that platinum drugs of equitoxic dose had similar effects on most of proteins in STAT3 pathway for 24 h. During early time course of drug administration, cisplatin(1μg/ml) elevated expression of pSTAT3(Tyr705), STAT3α, VEGF, survivin and Bcl-XL which promote ovarian cancer progression, while 8μg/ml oxaliplatin and 8μg/ml nedaplatin exhibited opposite effects and up-regulated pSTAT3(Ser727), STAT3β which may inhibit STAT3 activity to reverse cisplatin resistance.Conclusions: Effects of cisplatin on STAT3 pathway during early period may play an important role in its final resistance, which might explain the emergence of drug resistance. Thus, oxaliplatin and nedaplatin had opposite effects which might explain their effectiveness over cisplatin. Early responses of STAT3 pathway to platinum drugs associate with cisplatin-resistance in epithelial ovarian cancer and provide a rationale for new therapeutic strategies in reversing cisplatin-resistance. Focusing on early period of effects induced by chemotherapy agents might provide new perspectives in understanding of drug-resistance.