Abstract A230: An anti-leishmanial thiadiazine agent induces multiple myeloma cell apoptosis by suppressing the nuclear factor kappaB signaling pathway.

Nuclear factor kappaB (NF-κB) is a nuclear transcription factor that regulates expression of a large number of genes critical for cell proliferation, survival, inflammation, and tumorigenesis. Recent evidence indicates that NF-κB and its signaling pathways are constitutively activated both in myeloma cell lines and in primary myeloma cells. Downregulated NF-κB signaling by bortezomib and other compounds has demonstrated that the NF-κB signaling could be a promising therapeutic target of MM. In the present study, we found that one of the tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives displayed potent anti-myeloma activity by inhibiting the NF-κB signaling pathway. DETT downregulated IKKα, β, p65, and p50 expression and inhibited phosphorylation of p65 (Ser536) and IBα. Simultaneously, DETT increased IκBα, an inhibitor of the p65/p50 heterodimer, even in the presence of stimulants lipopolysacharride, tumor necrosis factor alpha or interleukin-6. DETT inhibited NF-κB transcription activity and down-regulated NF-κB targeted genes including Bcl-2, Bcl-XL, and XIAP. Deregulation of NF-κB signaling by DETT resulted in MM cell apoptosis characterized by cleavage of caspase-3, caspase-8, and PARP. Notably, this apoptosis was partly blocked by activation of NF-κB signaling in the presence of TNFα and IL-6. Moreover, DETT delayed myeloma tumor growth in nude mice without overt toxicity. DETT is therefore a potent candidate for MM therapy as an inhibitor of the NF-κB signaling pathway. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A230. Citation Format: Guodong Chen, Kunkun Han, Xin Xu, Xiaolin Du, Zubin Zhang, Juan Tang, Min Shi, Man Wang, Jie Li, Biyin Cao, Xinliang Mao. An anti-leishmanial thiadiazine agent induces multiple myeloma cell apoptosis by suppressing the nuclear factor kappaB signaling pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A230.