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

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

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 16 , Issue 3 , 2021


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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.

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

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Article Details

VOLUME: 16
ISSUE: 3
Year: 2021
Published on: 24 February, 2021
Page: [350 - 362]
Pages: 13
DOI: 10.2174/1574892816666210224155403
Price: $95

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