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.
Keywords:
PI3K/AKT inhibition; anti-cancer agent; cytotoxicity; isoflavone analog; ovarian cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / metabolism
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Benzopyrans / pharmacology*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cisplatin / pharmacology*
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects*
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Female
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G2 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Hydrazones / pharmacology*
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Isoflavones / pharmacology*
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Mice, Inbred BALB C
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Mice, Nude
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / pathology
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Molecular Targeted Therapy
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology
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Phosphatidylinositol 3-Kinase / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / metabolism*
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Time Factors
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Transfection
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Benzopyrans
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Cell Cycle Proteins
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Hydrazones
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Isoflavones
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N'-(7-hydroxy-3-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-ylidene)acetohydrazide
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MTOR protein, human
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Cisplatin