Radotinib, a medicine for chronic myeloid leukemia, induces cell death of mantle cell lymphoma cells

Abstract Background: Radotinib is a medicine for the treatment of some types of cancer. It is approved in South Korea for use as a second-line treatment of chronic myeloid leukemia (CML). Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and of platelet-derived growth factor receptor (PDGFR). It has been little known the effects of radotinib on mantle cell lymphoma cells (MCL). Methods: First, we examined cytotoxicity of radotinib on MCL cell line, MAVER-1 and REC-1. Also, cytotoxicity of radotinib on both cell lines which have a different genetic back ground. Annexin V positive cell, caspas-3 and -9 activities, cell cycle distribution and mitochondrial membrane potential (MMP) were observed by analyzed with flow cytometric analysis. And diverse signaling pathways were investigated by Western blotting in MCL cells. Results: Interestingly, radotinib caused cell death of MCL cells. And radotinib induces G1-phase arrest in MAVER-1 and REC-1 cells. And it also inhibited the expression of CDK2, CDK4, and cyclin D1, D3 and E. Therefore, radotinib induces G1-phase arrest via suppression of CDK2, CDK4, and cyclin D1, D3 and E. Generally, the intrinsic apoptotic pathway involves mitochondrial activation and caspase and phosphatidylserine externalization. Radotinib induced Annexin V positive cells, and caspase pathway activation including caspase-3, -7 and -9. And its treatment remarkably decreased MMP in MCL cells at 72 h. As well as we observed that cytochrome c accumulated dose dependently in the cytosol of radotinib-treated MAVER-1 and REC-1 cells. Moreover, radotinib decreased the expression of Bcl-xL and Bcl-2, and increased the expression of Bax in MCL cells. These results indicate that radotinib induces cell death of MCL cells by induction of G1-phase arrest and mitochondrial-dependent apoptosis. Furthermore, the expression of p-AKT, AKT and ERK was significantly reduced by radotinib in MCL cells. Conclusion: Radotinib may play an important role as a candidate or chemosensitizer for treatment agent in MCL. These data indicate that radotinib has a potential for anti-cancer therapy in MCL. Citation Format: Sook-Kyoung Heo, Eui-Kyu Noh, Yoo Kyung Jeong, Jeong Yi Kim, Yunsuk Choi, Jaekyung Cheon, SuJin Koh, Jin Ho Baek, Young Joo Min, Jae-Cheol Jo. Radotinib, a medicine for chronic myeloid leukemia, induces cell death of mantle cell lymphoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1621.