Inhibition of the IL-6-Stat3 pathway and reversal of Taxol and cisplatin resistance in drug resistant ovarian cancer cell lines by a synthetic triterpenoid CDDO-Me

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Previous studies have identified interleukin 6 (IL-6) as an important cytokine with prognostic significance in ovarian cancer. Work in several laboratories supports the hypothesis that autocrine or paracrine stimulation of the IL-6-Stat3 pathway contributes to tumor cell growth, survival and drug resistance in several cancers including ovarian cancer. Prior studies have also demonstrated that recurrent ovarian tumors or tumors with dense inflammatory infiltrates frequently demonstrate Stat3 pathway activation. To explore potential therapeutic strategies for interrupting signaling through this pathway, we explored the ability of CDDO-Me, a synthetic triterpenoid, to inhibit IL-6 secretion, Stat3 phosphorylation, Stat3 nuclear translocation and paclitaxel sensitivity in several cell line model systems. In vitro studies demonstrated that CDDO-Me (at 0.1 to 0.3 μM) significantly inhibits IL-6 secretion in Taxol resistant ovarian cancer cells and specifically suppresses IL-6 or Oncostatin M- induced Stat3 nuclear translocation. Treatment with CDDO-Me significantly decreases the levels of Stat3, Jak2, and Src phosphorylaton in ovarian and breast cancer cell lines that have constitutively activated Stat3. This inhibition of the IL-6-Stat3 pathway correlated with suppression of the anti-apoptotic Stat3 target genes Bcl-X_L, survivin and Mcl-1, and induced apoptosis as measured by monitoring PARP and its cleavage product. Furthermore, CDDO-Me (0.3 μM) increases the cytotoxic effects of Taxol in the Taxol resistant ovarian cancer cell line OVCAR8_TR (2 to 5 fold) and cisplatin in the cisplatin resistant ovarian cancer cell line A2780cp70 (4 to 6 fold). In conclusion, our data confirm that CDDO-Me interrupts signaling through multiple kinases involved in the IL-6-Stat3 and Src signaling pathways. Inhibition is likely achieved through multiple points within these pathways. In a model system of established acquired drug resistance CCDO-Me is effective at partially reversing the drug resistance phenotype.