RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway.
RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway.
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RY-2f 是一种异黄酮类似物，通过靶向 PI3K/AKT/mTOR 信号通路克服顺铂耐药性，抑制卵巢肿瘤发生
DOI：
10.18632/oncotarget.4634
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Liu M;Qi Z;Liu B;Ren Y;Li H;Yang G;Zhang Q
卵巢癌仍然是妇科恶性肿瘤的主要死亡原因，部分原因是对化疗的抵抗。在本研究中，我们发现RY-2f是一种化学合成的异黄酮类类似物，通过上调p21、Cyclin B1、Bax、Bad和裂解PARP，以及抑制Cyclin A、CDK2和Bcl2，抑制卵巢癌细胞的增殖，使细胞周期停滞在G2/M期，并诱导细胞凋亡。细胞增殖和集落形成实验表明，RY-2F可提高顺铂的化疗效果，提示RY-2F与顺铂有协同作用。机制研究表明，RY-2f主要通过抑制PI3K/AKT/mTOR信号通路发挥抗肿瘤作用。最后，体内研究表明，在治疗剂量下，RY-2f抑制A2780诱导的移植瘤的生长，而在动物中没有检测到毒性，而RY-2f使顺铂耐药细胞系A2780/CDDP诱导的移植瘤对顺铂治疗再次增敏。因此，RY-2f有可能成为治疗卵巢癌的潜在药物。
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.