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

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

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

MeSH terms

  • Apoptosis / drug effects*
  • Benzofurans / pharmacology*
  • Carcinoma, Ovarian Epithelial / drug therapy*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Synergism
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • Humans
  • Leupeptins / pharmacology
  • Naphthoquinones / pharmacology*
  • Ovarian Neoplasms / drug therapy*
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors / pharmacology
  • STAT3 Transcription Factor / antagonists & inhibitors*

Substances

  • Benzofurans
  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Naphthoquinones
  • Proteasome Inhibitors
  • STAT3 Transcription Factor
  • napabucasin
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde