RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway.
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.
Cancer Institute, Fudan University Shanghai Cancer Center; and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Mingming
M
Liu
Cancer Institute, Fudan University Shanghai Cancer Center; and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Zihao
Z
Qi
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Bingzhi
B
Liu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Yi
Y
Ren
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Hanbin
H
Li
Cancer Institute, Fudan University Shanghai Cancer Center; and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
Gong
G
Yang
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Qian
Q
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001578:Benzopyrans; D018797:Cell Cycle Proteins; D006835:Hydrazones; D007529:Isoflavones; C000609206:N'-(7-hydroxy-3-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-ylidene)acetohydrazide; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin
PI3K/AKT inhibition; anti-cancer agent; cytotoxicity; isoflavone analog; ovarian cancer