Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden.
OBJECTIVES
Stat3 is persistently activated in ovarian cancer cells, with a crucial role in tumour onset and progression. In this study, we examined the anti-tumour effect of a small-molecule inhibitor napabucasin (BBI608) on epithelial ovarian cancer (EOC) in vitro and in vivo, and investigated the underlying molecular mechanism of this drug in combination with paclitaxel.


MATERIALS AND METHODS
A total of 156 ovarian cancer patient samples were analysed to determine the correlation between pStat3 expression in tumour cells and the prognosis of EOC patients. The anti-tumour effect of BBI608 and/or paclitaxel on ovarian cancer in vitro was evaluated by CCK-8, flow cytometry, Western blot and transwell assays. An in vivo intraperitoneal model was performed to confirm the effect of BBI608 on pStat3-mediated peritoneal metastasis when combined with paclitaxel.


RESULTS
Patients with high expression of pStat3 had poorer overall survival and progression-free survival than those with low pStat3 expression. The synergy of BBI608 in combination with paclitaxel exerted dramatic growth inhibition and induced apoptosis in EOC cell lines. In vivo, the combination of two drugs significantly decreased intraperitoneal tumour burden and ascites volume, prolonged survival of tumour-bearing mice compared with each monotherapy; these results were associated with downregulation of phospho-Stat3 and activation of apoptosis pathway.


CONCLUSIONS
Targeting the activation of Stat3 may be a potential therapeutic approach for EOC by acting synergistically with paclitaxel.
['Li|Hongyi|H|', 'Qian|Yanping|Y|', 'Wang|Xi|X|', 'Pi|Ruyu|R|', 'Zhao|Xia|X|https://orcid.org/0000-0001-6162-4931', 'Wei|Xiawei|X|https://orcid.org/0000-0002-6513-6422']
D000328:Adult D000368:Aged D000818:Animals D017209:Apoptosis D000077216:Carcinoma, Ovarian Epithelial D045744:Cell Line, Tumor D015536:Down-Regulation D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D051379:Mice D008807:Mice, Inbred BALB C D008875:Middle Aged D009363:Neoplasm Proteins D010051:Ovarian Neoplasms D017239:Paclitaxel D050796:STAT3 Transcription Factor D023041:Xenograft Model Antitumor Assays
paclitaxel apoptosis epithelial ovarian cancer Napabucasin (BBI608) Stat3 inhibitor