An anti-leishmanial thiadiazine agent induces multiple myeloma cell apoptosis by suppressing the nuclear factor kappaB signalling pathway

Abstract

Background:Nuclear factor κB (NFκB) has a critical role in the pathophysiology of multiple myeloma. Targeting NFκB is an important strategy for anti-myeloma drug discovery.Methods:Luciferase assay was used to evaluate the effects of DETT on NFκB activity. Annexin V-PI double staining and immunoblotting were used to evaluate DETT-induced cell apoptosis and suppression of NFκB signalling. Anti-myeloma activity was studied in nude mice.Results:DETT downregulated IKKα, β, p65, and p50 expression and inhibited phosphorylation of p65 (Ser536) and IκBα. Simultaneously, DETT increased IκBα, an inhibitor of the p65/p50 heterodimer, even in the presence of stimulants lipopolysaccharide, tumour necrosis factor-α, or interleukin-6. DETT inhibited NFκB transcription activity and downregulated NFκB-targeted genes, including Bcl-2, Bcl-XL, and XIAP as measured by their protein expression. Deregulation of NFκB signalling by DETT resulted in MM cell apoptosis characterised by cleavage of caspase-3, caspase-8, and PARP. Notably, this apoptosis was partly blocked by the activation of NFκB signalling in the presence of TNFα and IL-6. Moreover, DETT delayed myeloma tumour growth in nude mice without overt toxicity.Conclusion:DETT displays a promising potential for MM therapy as an inhibitor of the NFκB signalling pathway. © 2014 Cancer Research UK.