Qing Fang,* Siyi Jiang,* Chengyuan Li Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengyuan LiThe Third Xiangya Hospital of Central South University, Tongzipo Road 138, Changsha 410013, People’s Republic of ChinaTel/Fax +86 073188618511Email lcy800097@163.comIntroduction: Evodiamine (Evo) is one of the main bioactive components derived from the drying mature fruit of the genus Evodia rutaecarpa (Juss.) Benth. Although Evo has shown its anti-cancer activity in several cancers, the effects on multiple myeloma (MM) remain unknown. In this study, we aim to investigate the cytotoxic role of Evo on MM cells.Methods: CCK-8 assay, apoptotic cell analysis, xenografted mice model, caspase activity assay and mitochondrial membrane potential assay were performed.Results: We found that Evo selectively inhibits cell proliferation and increases apoptosis rate in MM cells, but not in healthy B lymphocytes, in a time and dose-dependent manner. Evo treatment significantly activated caspase-3 and −9 in MM cells. Evo also increased cytochrome C expression and ROS production in cytosol in a dose-dependent manner, which was abolished by MitoTEMPO cotreatment. In addition, co-treatment with bortezomib and Evo showed a more potent reduction of cell viability and a higher apoptosis than that of bortezomib single treatment in U266 and RPMI8226 cells.Conclusion: We provided evidence to demonstrate that Evo selectively suppresses cell growth and increases apoptosis rate in MM cells through the intrinsic apoptosis pathway. Application of Evo and bortezomib might enhance the anti-cancer effect on MM cells.Keywords: evodiamine, mitochondria, intrinsic apoptosis, bortezomib, resistance