AZD4547 and the Alleviation of Hepatoma Cell Sorafenib Resistance via the Promotion of Autophagy

Abstract

Background: This study is part of a larger research effort to explore the molecular mechanism of hepatocellular carcinoma, reduce drug resistance and seek new targets. Objective: To investigate the effect and mechanism of fibroblast growth factor receptor inhibitor AZD4547 on Sorafenib-resistant hepatoma cells. Methods: First we constructed a Sorafenib-resistant hepatoma cell line Huh7R. Different groups of Huh7R cells were treated with Sorafenib, AZD4547, Sorafenib combined with AZD4547, and normal saline. The cell viability was detected by Cell Counting Kit-8. Then Fibroblast growth factor receptor and Toll-like receptor 4 were detected by Western blot, as well as the LC3 II/I, Beclin1, and P62. In addition, we used the autophagy inhibitor 3-methyladenine to identify the mechanism of AZD4547 combined with Sorafenib for inducing Sorafenib-resistant hepatoma cell death. Results: We find that AZD4547 combined with Sorafenib significantly inhibited the viability of Sorafenib-resistant hepatoma cell Huh7R. As for its mechanism, AZD4547 was able to inhibit fibroblast growth factor receptor activity, promote autophagy and regulate immunity. AZD4547 increased LC3 II/I, Beclin1, and Toll-like receptor 4 proteins, and decreased P62 protein level in Huh7R cells significantly when given in combination with sorafenib. Furthermore, 3-methyladenine inhibited autophagy and reversed the killing effect of the combination of AZD4547 and Sorafenib on Huh7R cells. Conclusion: The inhibition of fibroblast growth factor receptor activity by AZD4547 can significantly enhance autophagy and immune response, as well as promote the death of Sorafenib-resistant hepatoma cells.

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“…Likewise, a reduced autophagy was directly related to the development of sorafenib resistance derived from SREBP cleavage-activating protein (SCAP) in an in vitro HCC model 195 . Sensitivity to sorafenib of Huh-7 cells with acquired resistance to this drug was augmented after inducing autophagy with the inhibitors BEZ235 196 and AZD4547 197 , showing even an increased migration of HCC cells without autophagy induction 196 . Contrariwise, a promoter role of autophagy on drug responsiveness has been also described in other HCC models, where osteopontin led to higher autophagy and, in consequence, to resistance acquisition against the chemotherapeutic agents epirubicin and cisplatin 198 .…”