RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway
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Mingming Liu1,*, Zihao Qi1,*, Bingzhi Liu2,*, Yi Ren2, Hanbin Li2, Gong Yang1,3, Qian Zhang2
1Cancer Institute, Fudan University Shanghai Cancer Center; and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
2Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
3Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
*These authors have contributed equally to this work
Gong Yang, e-mail: [email protected]
Qian Zhang, e-mail: [email protected]
Keywords: ovarian cancer, anti-cancer agent, isoflavone analog, PI3K/AKT inhibition, cytotoxicity
Received: January 18, 2015 Accepted: July 20, 2015 Published: July 30, 2015
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.
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