STAT3 抑制剂萘泊昔康抑制人卵巢癌细胞的生长并与蛋白酶体抑制剂协同作用。

STAT3 Inhibitor Napabucasin Inhibits Tumor Growth and Cooperates with Proteasome Inhibition in Human Ovarian Cancer Cells.

机构信息

Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.

Department of Otorhinolaryngology Head and Neck Surgery, Key Laboratory of Auditory Speech and Balance Medicine, Institute of Otolaryngology of Tianjin, Tianjin First Central Hospital, Tianjin 300192, China.

出版信息

Recent Pat Anticancer Drug Discov. 2021;16(3):350-362. doi: 10.2174/1574892816666210224155403.

DOI:10.2174/1574892816666210224155403

PMID:33655847

Abstract

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.

摘要

背景

卵巢癌是妇科恶性肿瘤中死亡率最高的疾病。STAT3 通路的激活与多种癌症（包括卵巢癌）的肿瘤进展和转移密切相关。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 作为单一药物或与蛋白酶体抑制剂 MG-132 联合应用于卵巢癌细胞中的抗肿瘤活性。

方法

MTT 法测定 Napabucasin 对卵巢癌 SKOV-3 细胞的抗增殖作用。通过流式细胞术、qRT-PCR 和 Western blot 探讨其抗肿瘤机制。使用 MDC 染色和串联 mRFP-GFP-LC3 荧光显微镜分析 Napabucasin 联合或不联合 MG-132 诱导自噬的能力。根据 Chou 和 Talalay（1984）的方法评估 Napabucasin 与 MG-132 的联合抗癌作用。

结果

Napabucasin 对 SKOV-3 细胞表现出明显的肿瘤抑制作用。Napabucasin 处理导致细胞周期阻滞在 G2/M 期。机制上，p21 的高表达可能有助于细胞周期的阻滞。此外，我们通过多种检测方法，包括 MDC 染色、自噬流检测和自噬标记物检测，证明 Napabucasin 在 SKOV-3 细胞中诱导自噬。此外，Napabucasin 与 MG-132 联合应用具有显著的协同抗增殖作用，可能通过线粒体依赖性途径诱导细胞凋亡。两种化合物诱导了促生存自噬，联合使用自噬抑制剂可能进一步增强它们的抗肿瘤作用。