Coordinative Activities of STAT3 Inhibitor BP-1-102 and Sorafenib Against Proliferation, Angiogenesis and EMT in Hepatocellular Carcinoma

Abstract

Abstract Sorafenib, the only standard chemotherapeutic drug for unresectable hepatocellular carcinoma (HCC), exerted unsatisfactory efficacy and resistance in HCC treatment, raising the urgent need to develop effective therapeutic strategies. Based on clinical studies where constitutively activated signal transducer and activator of transcription 3 (STAT3) was observed in patients resistant to sorafenib, we evaluated if an “add-on” strategy can be developed using STAT3 inhibitor, BP-1-102, to potentiate therapeutic outcomes. This strategy aims to reduce sorafenib dosages to avoid adverse systemic reactions and inhibit carcinogenesis to prevent disease relapse. In this study, the in vitro effects of this strategy were examined using proliferation assay, invasion assay, tube formation assay, western analysis, etc. In vivo effects were studied using the ectopic and orthotopic HCC models in athymic BALB/c nude mice. Our results showed that the combination of sorafenib and BP-1-102 synergistically inhibited cellular proliferation, angiogenesis, progression of epithelial-mesenchymal transition (EMT), and metastasis both in vitro and in vivo. Mechanism studies revealed that BP-1-102 enhanced the therapeutic effect of sorafenib by coordinatively reducing the transcriptional level of oncogenic STAT3 by reversing the level of p-STAT3(Ser727) which was inhibited by sorafenib. Besides, our findings clearly indicated that STAT3 (Ser727) could repress the STAT3 (Tyr705) level and lead to decreased transcriptional activity of STAT3. Our findings indicate that STAT3 inhibitor is a highly potent sorafenib adjuvant in cancer therapy deserving further development.