Background: Ovarian cancer is a disease with the highest mortality in gynecologic malignancies. Activation of STAT3 pathway is well known to be associated with tumor progression and metastasis in a number of cancers, including ovarian cancer. Therefore, STAT3 may be an ideal target for ovarian cancer treatment.

Objective: The present study aims to determine the antitumor activity of STAT3 inhibitor Napabucasin as a single agent or in combination with proteasome inhibitor MG-132 in ovarian cancer cells.

Methods: MTT was performed to determine the anti-proliferative effect of Napabucasin on ovarian cancer SKOV-3 cells. The involved anti-tumor mechanism was explored by flow cytometry, qRTPCR and western blot. MDC staining and tandem mRFP-GFP-LC3 fluorescence microscopy were used to analyze the autophagy-inducing capability of Napabucasin with or without MG-132. The combinational anticancer effect of Napabucasin and MG-132 was evaluated according to Chou and Talalay’s method (1984).

Results: Napabucasin showed obvious tumor-inhibitory effects against SKOV-3 cells. Treatment by Napabucasin arrested cell cycle progression in G2/M phase. Mechanistically, elevated expression of p21 may contribute to the blockade of the cell cycle. Moreover, we demonstrated that Napabucasin induced autophagy in SKOV-3 cells by using various assays, including MDC staining, autophagic flux examination, and detection of the autophagy markers. In addition, a combination of Napabucaisin with MG-132 exhibited a significant synergistic anti-proliferative effect, probably by inducing apoptosis through a mitochondria-dependent pathway. The two compounds induced pro-survival autophagies, and co-treatment with autophagy inhibiter might further enhance their antitumor effects.

Conclusion: Napabucasin alone or in combination with MG-132 might be promising treatment strategy for ovarian cancer patients.

背景：卵巢癌是妇科恶性肿瘤中死亡率最高的疾病。众所周知，STAT3 通路的激活与包括卵巢癌在内的许多癌症的肿瘤进展和转移有关。因此，STAT3可能是卵巢癌治疗的理想靶点。

目的：本研究旨在确定 STAT3 抑制剂 Napabucasin 作为单药或与蛋白酶体抑制剂 MG-132 联用在卵巢癌细胞中的抗肿瘤活性。

方法：采用MTT法测定萘布卡星对卵巢癌SKOV-3细胞的抗增殖作用。通过流式细胞术、qRTPCR和蛋白质印迹探讨了所涉及的抗肿瘤机制。MDC 染色和串联 mRFP-GFP-LC3 荧光显微镜用于分析 Napabucasin 与或不与 MG-132 的自噬诱导能力。根据 Chou 和 Talalay 的方法 (1984) 评估 Napabucasin 和 MG-132 的联合抗癌作用。

结果：Napabucasin对SKOV-3细胞具有明显的抑瘤作用。Napabucasin 治疗在 G2/M 期阻止细胞周期进展。从机制上讲，p21 的表达升高可能有助于细胞周期的阻断。此外，我们通过使用各种检测方法（包括 MDC 染色、自噬通量检测和自噬标志物检测）证明了 Napabucasin 在 SKOV-3 细胞中诱导自噬。此外，Napabucaisin 与 MG-132 的组合表现出显着的协同抗增殖作用，可能是通过线粒体依赖性途径诱导细胞凋亡。这两种化合物诱导了促生存的自噬，与自噬抑制剂共同治疗可能会进一步增强它们的抗肿瘤作用。

结论：Napabucasin 单独或联合 MG-132 可能是卵巢癌患者有希望的治疗策略。