Berberine increases the killing effect of pirarubicin on HCC cells by inhibiting ATG4B-autophagy pathway

Haiyan He; Meng He; Yunxia Wang; Haojun Xiong; Yu Xiong; Meihua Shan; Dong Liu; Ziyuan Guo; Yuhong Kou; Yan Zhang; Mingzhen Yang; Jiqin Lian; Liangbo Sun; Fengtian He

doi:10.1016/j.yexcr.2024.114094

Berberine increases the killing effect of pirarubicin on HCC cells by inhibiting ATG4B-autophagy pathway

Exp Cell Res. 2024 May 13;439(1):114094. doi: 10.1016/j.yexcr.2024.114094. Online ahead of print.

Authors

Haiyan He¹, Meng He², Yunxia Wang³, Haojun Xiong⁴, Yu Xiong³, Meihua Shan⁵, Dong Liu⁵, Ziyuan Guo⁵, Yuhong Kou⁵, Yan Zhang², Mingzhen Yang⁵, Jiqin Lian⁶, Liangbo Sun⁷, Fengtian He⁸

Affiliations

¹ Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China; Department of Laboratory Medicine, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
² Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China.
³ Department of Laboratory Medicine, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
⁴ Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
⁵ Department of Clinical Biochemistry, Army Medical University, Chongqing, 400038, China.
⁶ Department of Clinical Biochemistry, Army Medical University, Chongqing, 400038, China. Electronic address: lianjiqin@tmmu.edu.cn.
⁷ Department of Clinical Biochemistry, Army Medical University, Chongqing, 400038, China. Electronic address: 807125461@qq.com.
⁸ Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China. Electronic address: hefengtian66@aliyun.com.

PMID: 38750718
DOI: 10.1016/j.yexcr.2024.114094

Abstract

Pirarubicin (THP) is a new generation of cell cycle non-specific anthracycline-based anticancer drug. In the clinic, THP and THP combination therapies have been shown to be effective in hepatocellular carcinoma (HCC) patients with transcatheter arterial chemoembolization (TACE) without serious side effects. However, drug resistance limits its therapeutic efficacy. Berberine (BBR), an isoquinoline alkaloid, has been shown to possess antitumour properties against various malignancies. However, the synergistic effect of BBR and THP in the treatment of HCC is unknown. In the present study, we demonstrated for the first time that BBR sensitized HCC cells to THP, including enhancing THP-induced growth inhibition and apoptosis of HCC cells. Moreover, we found that BBR sensitized THP by reducing the expression of autophagy-related 4B (ATG4B). Mechanistically, the inhibition of HIF1α-mediated ATG4B transcription by BBR ultimately led to attenuation of THP-induced cytoprotective autophagy, accompanied by enhanced growth inhibition and apoptosis in THP-treated HCC cells. Tumor-bearing experiments in nude mice showed that the combination treatment with BBR and THP significantly suppressed the growth of HCC xenografts. These results reveal that BBR is able to strengthen the killing effect of THP on HCC cells by repressing the ATG4B-autophagy pathway, which may provide novel insights into the improvement of chemotherapeutic efficacy of THP, and may be conducive to the further clinical application of THP in HCC treatment.

Keywords: ATG4B; Berberine; Combination therapy; HCC; THP.