Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden.

Hongyi Li,Xia Zhao,Ruyu Pi,Yanping Qian,Xiawei Wei,Xi Wang

doi:10.1111/cpr.12719

Abstract

ObjectivesStat3 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 MethodsA 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.ResultsPatients 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.ConclusionsTargeting the activation of Stat3 may be a potential therapeutic approach for EOC by acting synergistically with paclitaxel.

Highlights

Epithelial ovarian cancer (EOC) refers to a gynaecologic malignancy exhibiting the largest lethality in the female population,[1] and doctors could not diagnose most cases with EOC until the disease displays late stage, noticeably promoting relapse and early death.[2]
EOC cells appear resistant to chemotherapy due to elevated activation of Signal transducer and activator of transcription 3 (Stat3).20 we examined whether targeting pSta[3] levels with BBI608 could sensitize EOC cells to pa‐ clitaxel
We found that subcytotoxic combinations of BBI608 and paclitaxel‐induced synergistic cell death in all three EOC cells (A2780, ID8 and SKOV3) tested (Figure 2A‐C, combination index (CI) < 1)

Summary

Introduction

Epithelial ovarian cancer (EOC) refers to a gynaecologic malignancy exhibiting the largest lethality in the female population,[1] and doctors could not diagnose most cases with EOC until the disease displays late stage, noticeably promoting relapse and early death.[2]. The majority of these patients eventually experience tumour relapse within two years because EOC cells either are less sensitive or become resis‐ tant to anti‐cancer drugs after consecutive therapy, resulting in a 5‐year survival rate as low as ~30%.5,6. For these reasons, treatment for EOC remains challenging, and there is an urgent need to develop more feasible agents exhibiting low toxicity with more distinct mo‐ lecular target in order to effectively assist in the treatment of ovar‐ ian cancers The majority of these patients eventually experience tumour relapse within two years because EOC cells either are less sensitive or become resis‐ tant to anti‐cancer drugs after consecutive therapy, resulting in a 5‐year survival rate as low as ~30%.5,6 For these reasons, treatment for EOC remains challenging, and there is an urgent need to develop more feasible agents exhibiting low toxicity with more distinct mo‐ lecular target in order to effectively assist in the treatment of ovar‐ ian cancers

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