Short Lecture "A withanolide analogue inhibits multiple myeloma cell proliferation through multiple signaling pathways"

Multiple myeloma is a hematological cancer originating from the bone marrow in which plasma cells abnormally proliferate and produce a large amount of monoclonal antibodies. It accounts for around 1% of cancer related deaths worldwide. Treatments using proteasome inhibitors, immunomodulators and monoclonal antibodies are currently used. However, those treatments have side effects, and drug resistance often appears. B-cell maturation antigen (BCMA) is a cell surface antigen found in nearly all cases of multiple myeloma, and needed for the survival of plasma cells. This makes it a key target for multiple myeloma therapeutics [1]. A withatholide analogue (W1), which displayed an IC₅₀ value around 80 nM against sensitive and bortezomib-resistant multiple myeloma cells, was identified. Moreover, its selectivity index towards normal cells was much more favourable than bortezomib, a proteasome inhibitor used in the clinics. Genomic and proteomic approaches were used to determine the genes and proteins involved in the mechanism of action of W1. Given the genes modulated by the compound and proteins it bound to, autophagy, a process that cells adopt to survive in unfavourable conditions by degrading and recycling non- essential proteins, was shown to be one of the involved pathways. Moreover, BCMA protein expression was down-regulated by 50-250 nM W1 starting 3 h after treatment and the inhibition was maintained for at least 48 h after removing W1. Given the strong current interest in BCMA-targeted treatment, W1 should be further evaluated alone or in combination in preclinical multiple myeloma models.

 

MissingLinkText

• References

• 1 Kleber M. et al. J Clin Med 2021; 10: 4088

Publikationsverlauf

Artikel online veröffentlicht:
16. November 2023