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

Mingming Liu; Zihao Qi; Bingzhi Liu; Yi Ren; Hanbin Li; Gong Yang; Qian Zhang

doi:10.18632/oncotarget.4634

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

Oncotarget. 2015 Sep 22;6(28):25281-94. doi: 10.18632/oncotarget.4634.

Authors

Mingming Liu¹, Zihao Qi¹, Bingzhi Liu², Yi Ren², Hanbin Li², Gong Yang^{1

3}, Qian Zhang²

Affiliations

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.

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

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism
Benzopyrans / pharmacology*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cisplatin / pharmacology*
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / drug effects*
Female
G2 Phase Cell Cycle Checkpoints / drug effects
Humans
Hydrazones / pharmacology*
Isoflavones / pharmacology*
Mice, Inbred BALB C
Mice, Nude
Mitochondria / drug effects
Mitochondria / metabolism
Mitochondria / pathology
Molecular Targeted Therapy
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / enzymology
Ovarian Neoplasms / genetics
Ovarian Neoplasms / pathology
Phosphatidylinositol 3-Kinase / metabolism*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction / drug effects*
TOR Serine-Threonine Kinases / metabolism*
Time Factors
Transfection
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
Benzopyrans
Cell Cycle Proteins
Hydrazones
Isoflavones
N'-(7-hydroxy-3-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-ylidene)acetohydrazide
MTOR protein, human
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Cisplatin