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

Background: Nuclear factor kappa B (NF kappa B) has a critical role in the pathophysiology of multiple myeloma. Targeting NF kappa B is an important strategy for anti-myeloma drug discovery. Methods: Luciferase assay was used to evaluate the effects of DETT on NF kappa B activity. Annexin V-PI double staining and immunoblotting were used to evaluate DETT-induced cell apoptosis and suppression of NF kappa B signalling. Anti-myeloma activity was studied in nude mice. Results: DETT downregulated IKK alpha, beta, p65, and p50 expression and inhibited phosphorylation of p65 (Ser536) and I kappa B alpha. Simultaneously, DETT increased I kappa B alpha, an inhibitor of the p65/p50 heterodimer, even in the presence of stimulants lipopolysaccharide, tumour necrosis factor-alpha, or interleukin-6. DETT inhibited NF kappa B transcription activity and downregulated NF kappa B-targeted genes, including Bcl-2, Bcl-XL, and XIAP as measured by their protein expression. Deregulation of NF kappa B 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 NF kappa B signalling in the presence of TNF alpha 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 NF kappa B signalling pathway.