Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells
| Autor: | Zeev Estrov, Shishir Shishodia, Raymond Alexanian, Michael Wang, M Amit-Vazina, David Harris, Donna M. Weber, Quin Van, Bharat B. Aggarwal, Moshe Talpaz |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
STAT3 Transcription Factor
Cancer Research Blotting Western Caspase 3 Apoptosis Electrophoretic Mobility Shift Assay Enzyme-Linked Immunosorbent Assay Biology Atiprimod hemic and lymphatic diseases Cell Line Tumor medicine Humans Spiro Compounds nuclear factor κB apoptosis Phosphorylation STAT3 Multiple myeloma HIV Long Terminal Repeat Cell growth Cell Cycle Cell cycle medicine.disease multiple myeloma DNA-Binding Proteins Enzyme Activation Oncology Caspases STAT protein Cancer research biology.protein Trans-Activators clonogenic assay Translational Therapeutics signal transduction |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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