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

[ Vol. 16 , Issue. 3 ]

Author(s):

Yao Liu, Xiaolin Peng, Hui Li, Wenhui Jiao, Xin Peng, Jingrong Shao, Yanglu Xu, Ran Wang*, Wei Wang* and Dexin Kong*   Pages 350 - 362 ( 13 )

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.

Affiliation:

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



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