Oncol Res. 2017 Sep 21;25(8):1245-1252. doi: 10.3727/096504017X14850164661097. Epub 2017 Jan 23.
Ovarian cancer is the most lethal disease among gynecological malignancies. More effective therapy is required to counter high recurrence rates and chemotherapy resistance. We investigated the efficacy and molecular mechanisms of three combined treatments (TCTs)-a novel histone deacetylase (HDAC) inhibitor OBP-801/YM753, 5-fluorouracil (5-FU), and paclitaxel (PTX)-in human ovarian cancer SKOV-3 and OVCAR-3 cells. The inhibition of cell growth was stronger with TCTs than with each single agent and with two combined treatments. The TCTs significantly induce G2 phase arrest in both cell lines. We then analyzed the molecular mechanisms and found that the TCTs increased the phosphorylation of p38 (Thr180/Tyr182), decreased the expression of CDC25C, and increased the phosphorylation of CDC2 (Tyr15), an inactive form of CDC2. To examine the responsibilities of the p38 pathway for G2 phase arrest induced by the TCTs, we employed the p38 inhibitor SB203580. SB203580 inhibited G2 phase arrest, suppression of CDC25C, and phosphorylation of CDC2 (Tyr15) induced by the TCTs. These results suggest that the TCTs can induce G2 phase arrest through activation of the p38 signaling pathway. We therefore believe that this combination is promising as a novel therapeutic strategy against ovarian cancer.
卵巢癌是妇科恶性肿瘤中最致命的疾病。需要更有效的治疗方法来对抗高复发率和化疗耐药性。我们研究了三种联合治疗（TCTs）——一种新型组蛋白去乙酰化酶（HDAC）抑制剂 OBP-801/YM753、5-氟尿嘧啶（5-FU）和紫杉醇（PTX）——在人卵巢癌 SKOV-3 和 OVCAR-3 细胞中的疗效和分子机制。与每种单一药物和两种联合治疗相比，TCTs 对细胞生长的抑制作用更强。TCTs 显著诱导两种细胞系的 G2 期停滞。然后，我们分析了分子机制，发现 TCTs 增加了 p38 的磷酸化（Thr180/Tyr182），降低了 CDC25C 的表达，并增加了 CDC2（Tyr15）的磷酸化，CDC2 是一种无活性形式。为了研究 p38 途径对 TCTs 诱导的 G2 期停滞的责任，我们使用了 p38 抑制剂 SB203580。SB203580 抑制了 TCTs 诱导的 G2 期停滞、CDC25C 的抑制和 CDC2（Tyr15）的磷酸化。这些结果表明，TCTs 可以通过激活 p38 信号通路诱导 G2 期停滞。因此，我们认为这种联合治疗是一种有前途的治疗卵巢癌的新策略。
