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Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu
Teru Hideshima1, Masaharu Akiyama, Toshiaki Hayashi
1Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Abstract:
p38 mitogen-activated protein kinase (MAPK) is a member of the MAPK family which is activated by cytokines and growth factors, but its role in pathogenesis of multiple myeloma (MM) is unknown. In this study, we demonstrate that the specific p38 MAPK inhibitor VX-745 inhibits interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in bone marrow stromal cells (BMSCs), without affecting their viability. Tumor necrosis factor alpha (TNF-alpha)-induced IL-6 secretion in BMSCs is also inhibited by VX-745. Importantly, VX-745 inhibits both MM cell proliferation and IL-6 secretion in BMSCs triggered by adherence of MM cells to BMSCs, suggesting that it can inhibit paracrine MM cell growth in the BM milieu and overcome cell adhesion-related drug resistance. These studies therefore identify p38 MAPK as a novel therapeutic target to overcome drug resistance and improve patient outcome in MM.
Insights
p38 mitogen-activated protein kinase (MAPK) inhibition reduces multiple myeloma (MM) cell growth and drug resistance. Targeting p38 MAPK may improve outcomes for MM patients by blocking key signaling pathways.
Area of Science:
- Molecular Biology
- Oncology
- Cell Signaling
Background:
- The role of p38 mitogen-activated protein kinase (MAPK) in multiple myeloma (MM) pathogenesis is not well understood.
- MAPK pathways are activated by cytokines and growth factors, influencing various cellular processes.
Purpose of the Study:
- To investigate the role of p38 MAPK in multiple myeloma.
- To evaluate the therapeutic potential of p38 MAPK inhibition in MM.
Main Methods:
- Utilized the specific p38 MAPK inhibitor VX-745.
- Assessed the effects of VX-745 on cytokine secretion (IL-6, VEGF) in bone marrow stromal cells (BMSCs).
- Examined the impact of VX-745 on MM cell proliferation and drug resistance, particularly in the context of MM cell adherence to BMSCs.
Main Results:
- VX-745 inhibited interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion from BMSCs without affecting cell viability.
- Tumor necrosis factor alpha (TNF-alpha)-induced IL-6 secretion in BMSCs was also suppressed by VX-745.
- VX-745 demonstrated efficacy in inhibiting MM cell proliferation and IL-6 secretion triggered by MM cell-BMSC adherence, suggesting a role in overcoming drug resistance.
Conclusions:
- p38 MAPK is identified as a novel therapeutic target in multiple myeloma.
- Inhibition of p38 MAPK may offer a strategy to overcome drug resistance and improve patient outcomes in MM.
- Targeting p38 MAPK could disrupt the paracrine signaling that supports MM cell growth within the bone marrow microenvironment.