Xiawei Wei

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

AbstractObjectivesStat3 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.

Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth

Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients' prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.

SB225002 Enhances Radiosensitivity in Cervical Cancer via Direct Neutrophil Inhibition and Tumor Cell Suppression.

Radiotherapy resistance is a major contributor to therapeutic failure in cervical cancer, largely due to the immunosuppressive tumor microenvironment (TME). Increasing clinical and experimental evidence underscores the role of neutrophils infiltration in reducing the efficacy of radiation therapy. Additionally, the CXCR2/CXCL signaling axis has been identified as a key regulator of neutrophils recruitment. Our study demonstrates that radiotherapy significantly enhances neutrophils infiltration by activating CXCR2-CXCL signaling and drives their polarization toward a pro-tumor N2-like phenotype through TGF-β signaling in cervical cancer. Further investigation revealed that CXCR2 antagonist SB225002 exerts a synergistic effect with radiotherapy and concurrent chemoradiotherapy in cervical cancer, primarily via inhibiting neutrophils infiltration and alleviating the immunosuppressive TME. Meanwhile, SB225002 exerts direct antitumor activity and enhances the radiosensitivity of cervical cancer cells by facilitating DNA double-strand breaks, promoting G2/M phase cell cycle arrest, and inducing apoptosis. In summary, our findings highlight neutrophils inhibition via CXCR2 antagonist as a promising therapeutic strategy to enhance cervical cancer responsiveness to radiotherapy.