Radotinib inhibits multiple myeloma cell proliferation via suppression of STAT3 signaling

PLoS One. 2022 May 3;17(5):e0265958. doi: 10.1371/journal.pone.0265958. eCollection 2022.

Abstract

Multiple myeloma (MM) is a hematological cancer causing from accumulated abnormal plasma cells. STAT3 overexpression in MM appears to be mediated by a variety of factors, and it may be associated with an adverse prognosis and play a role in microenvironment-dependent treatment resistance. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. It is an oral, multitargeted inhibitor of receptor tyrosine kinases, including BCR-ABL, c-KIT, PDGFR, and Src family kinases. However, little is known about the effects of radotinib on multiple myeloma cells. However, little is known about the effects of radotinib on multiple myeloma cells. But even tinip almost not known about the impact of multiple myeloma cells. Moreover, nothing is known about how it affects STAT3 and JAK2. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Herein, Moreover, nothing is known about how it. Moreover, not all is known about how the affects STAT3 and JAK2. We investigated the effect of radotinib on the STAT3 signaling pathway in MM cells, including several MM cell lines and mouse models. So we investigated the effect of radotinib on MM cells, including several MM cell lines and mouse models. Interestingly, radotinib induced apoptosis, and inhibited cell proliferation in MM cells including RPMI-8226, MM.1S, U266B1, and IM-9 cells. Moreover, radotinib treatment significantly increased the number Annexin V-positive cells and G0/G1-phase cells. In addition, radotinib treatment in various MM cells strongly suppressed the activity and expression of STAT3 and JAK2 proteins. We also observed that diverse proteins related to the STAT3 signaling pathway, including c-Myc, Bcl-xL, Mcl-1, cyclin D1 and cyclin D3, were powerfully inhibited by radotinib treatment in MM cells. Furthermore, radotinib significantly suppressed MM cell growth in a xenograft animal model using IM-9 cells. In conclusion, radotinib may play an important role as a candidate agent for MM treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Benzamides
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Mice
  • Multiple Myeloma* / drug therapy
  • Multiple Myeloma* / genetics
  • Multiple Myeloma* / metabolism
  • Pyrazines
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl)-3-(4-pyrazin-2-ylpyrimidin-2-ylamino)benzamide
  • Benzamides
  • Pyrazines
  • STAT3 Transcription Factor
  • STAT3 protein, human

Grants and funding

This work was supported by the Ulsan University Hospital Research Grant (UUH-2021-07). This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (NRF-2017R1A1A3A04069314, NRF-2021R1F1A1050975). This work was supported by the Biomedical Research Institute Grant, funded by the Ulsan University Hospital (2022-UUHBRI-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.