Cytokine-mediated modulation of cisplatin sensitivity in ovarian cancer cells

Abstract Background: Epithelial ovarian cancer cells are known to produce interleukin-6 (IL-6) and are known to express IL-6 receptors. Serum and peritoneal fluid concentrations of IL-6 are elevated in patients with epithelial ovarian cancers. Metallothioneins are a group of proteins with high affinity for heavy metal ions, including platinum; they are inducible by IL-6 and may confer resistance of ovarian cancer cells to cisplatin chemotherapy. Objective: To determine whether IL-6 induces cisplatin resistance in ovarian cancer cells and to assess whether it does so by increasing intracellular metallothionein. Methods: Two ovarian cancer cell lines (SKOV3, OC194) were incubated with either recombinant IL-6, anti-IL-6 antibody, anti-IL-6 receptor antibody, or IL-10 for 24 hours. Cisplatin was then added, and an MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) cytotoxicity assay was performed after 48 hours. Western blot probing for metallothionein was performed after a 24-hour incubation of SKOV3 cells with IL-6. Results: Pretreatment of ovarian cancer cells with IL-6 before adding cisplatin resulted in a significant reduction in cytotoxicity. Reversal of this IL-6 effect with anti-IL-6 antibody, anti-IL-6 receptor antibody, and IL-10 was demonstrated. Western blot analysis of IL-6–treated cells revealed a positive correlation between IL-6 exposure and cellular metallothionein content. Conclusion: These results demonstrate that expression of IL-6 by ovarian cancer cells confers resistance to cisplatin cytotoxicity by upregulation of metallothione. In addition, inhibition of IL-6 effect reverses this cisplatin resistance. Clinically, suppression of IL-6 effect may be exploited to potentiate cisplatin chemotherapy, leading to better survival rates in ovarian cancer patients.