Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells.

Abstract

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.

• Authors: M Amit-Vazina, S Shishodia, D Harris, Q Van, M Wang, D Weber, R Alexanian, M Talpaz, B B Aggarwal, Z Estrov
• Journal: British journal of cancer (Br J Cancer) Vol. 93 Issue 1 Pg. 70-80 (Jul 11 2005) ISSN: 0007-0920 [Print] England
• PMID: 15970928 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Spiro Compounds
• Trans-Activators
• azaspirane
• Caspases

Topics

• Apoptosis
• Blotting, Western
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Electrophoretic Mobility Shift Assay
• Enzyme Activation
• Enzyme-Linked Immunosorbent Assay
• HIV Long Terminal Repeat
• Humans
• Multiple Myeloma (metabolism, pathology)
• Phosphorylation
• STAT3 Transcription Factor
• Spiro Compounds (pharmacology)
• Trans-Activators (antagonists & inhibitors, metabolism)