Ruxolitinib synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer
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Ernest S. Han1, Wei Wen1,2, Thanh H. Dellinger1, Jun Wu3, Selena A. Lu1, Richard Jove2,4 and John H. Yim1
1Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
2Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
3Department of Comparative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
4Current/Present address: Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA
John H. Yim, email: [email protected]
Keywords: ruxolitinib; ovarian; paclitaxel; combination; synergy
Received: October 27, 2017 Accepted: January 19, 2018 Epub: January 31, 2018 Published: May 11, 2018
Treatment for ovarian cancer remains challenging despite a high initial response rate to first line platinum-taxane treatment. Most patients eventually experience recurrence and require further treatment. Persistent activation of STAT3 is associated with cancer growth and progression and is also involved in cell resistance to platinum and taxane treatment. Targeting JAK/STAT3, therefore, could be a potential novel therapeutic approach for treating advanced and chemoresistant ovarian cancer. We investigated the therapeutic potential of ruxolitinib, a JAK1/JAK2 inhibitor that has been FDA-approved for the treatment of myelofibrosis, to treat ovarian cancer either alone or in combination with conventional chemotherapy agents. We show that ruxolitinib inhibits STAT3 activation and ovarian tumor growth both in ovarian cancer cells and in an ovarian cancer mouse model. In addition, ruxolitinib significantly increases the anti-tumor activity of chemotherapy agents, including paclitaxel, cisplatin, carboplatin, doxorubicin and topotecan in ovarian cancer cells. Evaluation of the combination index (CI) shows that ruxolitinib synergistically interacts with paclitaxel in all three human ovarian cancer cells. Finally, our results demonstrate that combination of ruxolitinib and paclitaxel leads to a greater reduction of tumor growth compared to single treatment of either agent in a tumor mouse model that represents late stage ovarian cancer with peritoneal metastasis and ascites formation. Taken together, our findings provide a foundation for clinical trials with ruxolitinib, either as a single agent or in combination with paclitaxel, for the treatment of recurrent and advanced ovarian cancer.
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