Radotinib inhibits multiple myeloma cell proliferation via suppression of STAT3 signaling

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.

An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

“…Multiple STAT3-inhibitors are currently under investigation for their application in cancer 53 , including myeloma 54 , where STAT3 inhibition additionally inhibits proliferation of myeloma cells 55,56 .…”

“…Although our analysis did not lead to identification of the iMSC-derived signals activating neutrophils via STAT3, the STAT3 dependency may provide opportunity for therapeutic intervention of pro-tumor inflammation in the MM bone marrow. Multiple STAT3-inhibitors are currently under investigation for their application in cancer 53 , including myeloma 54 , where STAT3 inhibition additionally inhibits proliferation of myeloma cells 55, 56 .…”

Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment

“…Each component of the STAT family has 6 homologous sequences, such as a helical helix motif, a spacer motif, an N-terminal oligomerization motif, a C-terminal transcription motif, an Src homology 2 motif, and a DNA-binding domain. Importantly, each STAT has a tyrosine necessary for DNA attachment, oligomerization, and nuclear transport located near the Src homology region ( Heo et al, 2022 ). Several STATs have been linked to carcinogenesis, but STAT1, STAT3, and STAT5 are strongly intertwined with HNSCC ( Yang M. et al, 2022 ).…”

“…PI3K is subsequently stimulated, which results in a rise in PIP3 then activating the essential protein kinase B (PKB or Akt) via phosphorylation (Ma G. et al, 2022). The anti-apoptotic molecule Bcl-2 is consequently released from Bad by PKB, which also promotes mTOR to initiate protein production and hinders GSK-3β to improve glucose utilization (Lee J. S. et al, 2022). It is known as the PI3K/PKB cascade of IGF-1R regulation and is primarily essential for cell death (Choi, 2022).…”

“…In 2011, genomic microarray results confirmed that upregulation of the circuit (in the case of HNSCCs) is favored by 6%-20% genetic variations in PI3KCA genes encoding p110α. Moreover, 80% of genetic variations unfold in exon 4, exon 20 (kinase unit), and exon 9 (helical unit), mainly via paradigms of genomic modulation (Lee S. Y. et al, 2022). Interestingly, PTEN alterations (phosphatase and tensin homolog) were detected in 10% of HNSCC incidences, although they may not represent the predominant pathway for PTEN depletion in HNSCC (Squarize et al, 2013).…”