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


CONCLUSIONS
DETT displays a promising potential for MM therapy as an inhibitor of the NFκB signalling pathway.
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
G
G
Chen
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
K
K
Han
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
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X
Xu
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
X
X
Du
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Z
Z
Zhang
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
J
J
Tang
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
M
M
Shi
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
M
M
Wang
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
J
J
Li
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
B
B
Cao
1] Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China [2] Department of Pharmacology, College of Pharmacy, Soochow University, Suzhou 215123, China.
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X
Mao
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D048708:Cell Growth Processes / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D013829:Thiadiazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D013829:Thiadiazines; D000069286:Bortezomib