A potent oncolytic adenovirus selectively blocks the STAT3 signaling pathway and potentiates cisplatin antitumor activity in ovarian cancer

摘要

Cisplatin-centered chemotherapy is the first-line treatment for human ovarian cancer. However, chemoresistance remains a major obstacle to successful treatment. Evidence has indicated that signal transducer and activator of transcription-3 (STAT3) is a determinant of chemoresistance; it was related to tumor recurrence in a large number of solid malignancies. Unfortunately, none of the compounds currently developed to block STAT3 signaling has been considered a serious clinical candidate because of toxicity or limited bioavailability. In this study, we clarified the significance of STAT3 activation in chemoresistant ovarian cancer and assessed the suitability of a novel oncolytic adenovirus (M4) designed to specifically deplete STAT3 and reverse cisplatin resistance in ovarian cancer. We showed that aberrant expression and constitutive activation of STAT3 was instrumental in cisplatin resistance in ovarian cancer cell lines and in ovarian cancer tissue samples. The M4 adenovirus could specifically deplete constitutive and inducible STAT3 and phosphorylated STAT3 proteins in ovarian cancer cells. This significantly inhibited cell survival and enhanced cisplatin-induced apoptosis. In contrast, normal human umbilical vein endothelial cells and human ovarian surface epithelial cells appeared to be unaffected by M4 treatment. Furthermore, a combined cisplatin plus M4 therapy substantially eliminated populations enriched in tumor-initiating cells. In mice, systemic intraperitoneal administration of M4 significantly potentiated the antitumor effect of cisplatin. These results suggest that M4 has great potential as a therapy against cisplatin resistance in human ovarian cancer. Thus, it warrants further clinical investigation.