RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway

// Mingming Liu 1, * , Zihao Qi 1, * , Bingzhi Liu 2, * , Yi Ren 2 , Hanbin Li 2 , Gong Yang 1, 3 , Qian Zhang 2 1 Cancer Institute, Fudan University Shanghai Cancer Center; and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 2 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China 3 Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China * These authors have contributed equally to this work Correspondence to: Gong Yang, e-mail: yanggong@fudan.edu.cn Qian Zhang, e-mail: zhangqian511@shmu.edu.cn Keywords: ovarian cancer, anti-cancer agent, isoflavone analog, PI3K/AKT inhibition, cytotoxicity Received: January 18, 2015      Accepted: July 20, 2015      Published: July 30, 2015 ABSTRACT Ovarian cancer remains the leading cause of death in gynecologic malignancies partially because of resistance to chemotherapy. In the present study, we show that RY-2f, a chemically synthesized isoflavone analog, inhibited ovarian cancer cell proliferation, blocked cell cycle in G2/M phase and induced cellular apoptosis through up-regulation of p21, cyclin B1, Bax, Bad and cleaved-PARP, and suppression of cyclin A, CDK2 and Bcl-2. We also show that RY-2f could increase the chemotherapeutic efficacy of cisplatin as tested by cell proliferation and colony formation assays, indicating a synergistic effect of RY-2f and cisplatin. Mechanistic study revealed that RY-2f exerted the anti-tumor activities mainly through suppression of the PI3K/AKT/mTOR signaling. Finally, in vivo studies showed that RY-2f blocked the A2780-induced xenograft tumor growth without detectable toxicity in the animals at the therapeutic doses, and whereas RY-2f re-sensitized the cisplatin resistant cell line A2780/CDDP induced xenograft tumor to cisplatin treatment. Thus, RY-2f may be developed as a potential therapeutic agent to treat ovarian cancer.