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

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

Volume: 16 Issue: 3

Author(s): Yao Liu, Xiaolin Peng, Hui Li, Wenhui Jiao, Xin Peng, Jingrong Shao, Yanglu Xu, Ran Wang*, Wei Wang*Dexin Kong*

Affiliation:

• 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

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

Keywords: Ovarian cancer, STAT3, napabucasin, proteasome inhibitor, G2/M phase arrest, autophagy.

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.

Cite this article as:

Liu Yao , Peng Xiaolin , Li Hui, Jiao Wenhui , Peng Xin , Shao Jingrong , Xu Yanglu , Wang Ran*, Wang Wei *, Kong Dexin *, STAT3 Inhibitor Napabucasin Inhibits Tumor Growth and Cooperates with Proteasome Inhibition in Human Ovarian Cancer Cells, Recent Patents on Anti-Cancer Drug Discovery 2021; 16 (3) . https://dx.doi.org/10.2174/1574892816666210224155403