Molecular mechanism by which RRM2-inhibitor (cholagogue osalmid) plus bafilomycin A1 cause autophagic cell death in multiple myeloma

Shushan Guo; Zhijian Xu; Qilin Feng; Hui Zhang; Dandan Yu; Bo Li; Ke Hu; Xuejie Gao; Qikai Zhang; Hongfei Yi; Xiaosong Wu; Dongliang Song; Huabin Zhu; Haiyan Cai; Yu Peng; Weiliang Zhu; Jumei Shi

doi:10.1016/j.abb.2023.109771

Molecular mechanism by which RRM2-inhibitor (cholagogue osalmid) plus bafilomycin A1 cause autophagic cell death in multiple myeloma

Arch Biochem Biophys. 2023 Oct 1:747:109771. doi: 10.1016/j.abb.2023.109771. Epub 2023 Sep 28.

Authors

Shushan Guo¹, Zhijian Xu², Qilin Feng¹, Hui Zhang¹, Dandan Yu³, Bo Li², Ke Hu¹, Xuejie Gao¹, Qikai Zhang¹, Hongfei Yi³, Xiaosong Wu³, Dongliang Song³, Huabin Zhu³, Haiyan Cai¹, Yu Peng³, Weiliang Zhu⁴, Jumei Shi⁵

Affiliations

¹ Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
² State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
³ Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
⁴ State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: wlzhu@simm.ac.cn.
⁵ Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. Electronic address: shijumei@tongji.edu.cn.

PMID: 37776936
DOI: 10.1016/j.abb.2023.109771

Abstract

Despite significant improvement in the prognosis of multiple myeloma (MM), the disease remains incurable; thus, more effective therapies are required. Ribonucleoside-diphosphate reductase subunit M2 (RRM2) is significantly associated with drug resistance, rapid relapse, and poor prognosis. Previously, we found that 4-hydroxysalicylanilide (osalmid), a specific inhibitor of RRM2, exhibits anti-MM activity in vitro, in vivo, and in human patients; however, the mechanism remains unclear. Osalmid inhibits the translocation of RRM2 to the nucleus and stimulates autophagosome synthesis but inhibits subsequent autophagosome-lysosome fusion. We confirm that RRM2 binds to receptor-interacting protein kinase 3 (RIPK3) and reduces RIPK3, inhibiting autophagosome-lysosome fusion. Interestingly, the combination of osalmid and bafilomycin A1 (an autophagy inhibitor) depletes RIPK3 and aggravates p62 and autophagosome accumulation, leading to autophagic cell death. Combination therapy demonstrates synergistic cytotoxicity both in vitro and in vivo. Therefore, we propose that combining osalmid and bafilomycin A1(BafA1) may have clinical benefits against MM.

Keywords: Autophagy; Bafilomycin A1; Cholagogue osalmid; RIPK3; RRM2; p62.