Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells.
Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod (2-(3-Diethylaminopropyl)-8,8-dipropyl-2-azaspiro[4,5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a time- and dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G(0)/G(1) phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.
Amit-Vazina
M
M
Department of Bioimmunotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Shishodia
S
S
Harris
D
D
Van
Q
Q
Wang
M
M
Weber
D
D
Alexanian
R
R
Talpaz
M
M
Aggarwal
B B
BB
Estrov
Z
Z
D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D016325:HIV Long Terminal Repeat; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor; D013141:Spiro Compounds / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013141:Spiro Compounds; D015534:Trans-Activators; C099015:azaspirane; D020169:Caspases