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.
Highlights
Ovarian cancer accounts for only about 3% of all malignancies in women, but is the leading cause of death in female reproductive carcinomas [1]
The anti-proliferative activity of RY-2f was initially tested by using human ovarian carcinoma cells, including A2780, HEY and OVCA433 cell lines
In agreement with the in vitro data, RY-2f displays the activity to suppress in vivo A2780 xenograft tumor growth with little toxicity in tested animals at the therapeutic dose (Figure 6A-C)
Summary
Ovarian cancer accounts for only about 3% of all malignancies in women, but is the leading cause of death in female reproductive carcinomas [1]. Drug-resistance has been a major challenge in treatment of recurrent ovarian cancer [6]. Numerous investigations have demonstrated that the PI3K/AKT/mTOR signaling is commonly over-activated and plays an important role in the stimulation of proliferation, survival, metastasis, and drug-resistance in many cancer types [7,8,9,10]. Studies have shown that the activation of the PI3K/AKT/mTOR signal pathway contributes to the platinum-based resistance and poor prognoses in ovarian cancer [16,17,18]. To improve the sensitivity of ovarian cancer cells to platinum-based chemotherapy, targeting the PI3K/ATK/mTOR signal pathway has emerged as one of the major therapeutic strategies [19, 20]
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