Chidamide-Induced Accumulation of Reactive Oxygen Species Increases Lenalidomide Sensitivity Against Multiple Myeloma Cells

Duanfeng Jiang; Kaixuan Zhang; Yinghong Zhu; Yan Zhu; Lang Zou; Jian Hu; Yajuan Cui; Wen Zhou; Fangping Chen; Yanjuan He

doi:10.2147/OTT.S312249

Chidamide-Induced Accumulation of Reactive Oxygen Species Increases Lenalidomide Sensitivity Against Multiple Myeloma Cells

Onco Targets Ther. 2021 Jul 6:14:4061-4075. doi: 10.2147/OTT.S312249. eCollection 2021.

Authors

Duanfeng Jiang¹, Kaixuan Zhang², Yinghong Zhu³, Yan Zhu², Lang Zou², Jian Hu², Yajuan Cui⁴, Wen Zhou³, Fangping Chen^{1

2}, Yanjuan He²

Affiliations

¹ Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China.
² Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China.
³ Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, People's Republic of China.
⁴ Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.

Abstract

Background: Lenalidomide, an immunomodulatory drug (IMiD), is an effective therapy for the treatment of multiple myeloma (MM). However, prolonged treatment may be accompanied by toxicity, second primary malignancies, and drug resistance. There is an inherent vulnerability in MM cells that high rates of immunoglobulin synthesis resulting in the high level of reactive oxygen species (ROS). This provides a therapeutic potential for MM.

Materials and methods: The intracellular ROS levels, H₂O₂ production and glutathione (GSH) levels were measured using detection kit. Cell viability was evaluated using cell-counting kit-8 (CCK-8) and soft agar colony formation assay. Apoptosis was determined in whole living cells using flow cytometry. Chidamide and its anti-myeloma efficacy in combination with lenalidomide were characterized in MM cell lines in vitro and in a mouse xenograft model. Moreover, Western blotting, immunofluorescence and immunohistochemical studies were performed.

Results: ROS levels increased in a time- and dose-dependent manner with chidamide treatment. Moreover, the GSH levels were decreased and the mRNA level of SLC7A11 downregulated after chidamide treatment. The co-treatment with chidamide and lenalidomide increased apoptosis and proliferation inhibition, with combination index (CI) in the synergistic range (0.2-0.5) using the Chou-Talalay method. The cooperative anti-myeloma efficacy was confirmed in the murine model, and immunohistochemical studies also supported this potentiation. Chidamide enhanced the effect of lenalidomide-induced degradation of IKZF1 and IKZF3 by elevating H₂O₂. In addition, co-treatment with chidamide and lenalidomide increased biomarkers of caspase and DNA damage.

Conclusion: Elevated ROS production may constitute a potential biochemical basis for anti-myeloma effects of chidamide plus lenalidomide. The results of this study confirm the synergistic effect of chidamide and lenalidomide against MM and provide a promising therapeutic strategy for MM.

Keywords: chidamide; lenalidomide; multiple myeloma; reactive oxygen species.