Biological effects of the Pim kinase inhibitor, SGI-1776, in multiple myeloma.
BACKGROUND
Pim kinases are constitutively active serine/threonine/tyrosine kinases that are overexpressed in hematological malignancies such as multiple myeloma. Pim kinase substrates are involved in transcription, protein translation, cell proliferation, and apoptosis. SGI-1776 is a potent Pim kinase inhibitor that has proven to be cytotoxic to leukemia and lymphoma cells. Based on this background, we hypothesized that SGI-1776 treatment would result in myeloma cytotoxicity.


MATERIALS AND METHODS
To test this, myeloma cell lines and primary CD138(+) cells from myeloma patients were treated with SGI-1776 in a dose- and time-dependent manner, and effect on cell death and proliferation, induction of autophagy, and changes in cell cycle profile were measured.


RESULTS
SGI-1776 treatment resulted in limited apoptosis in cell lines (mean 30%) and CD138(+) cells (< 10%) assessed using Annexin-V/propidium iodide. Limited effect was observed in cell cycle profile or growth in cell lines. However, DNA synthesis was decreased by 70% at 3 μM (all time points) in U266 though this was not observed in MM.1S. In accordance, immunoblot analyses revealed no change in transcription (c-Myc and H3), or apoptotic (Bad) proteins that are substrates of Pim kinases. In contrast, autophagy, assessed using acridine orange staining, was induced with SGI-1776 treatment in both cell lines (U266, 25%-70%; MM.1S, 8%-52%) and CD138(+) cells (19%-21%). Immunoblot analyses of the autophagy LC3b marker and translation initiation proteins (phospho-p70S6K and 4E-BP1) corroborated autophagy induction.


CONCLUSION
These data indicate that SGI-1776 treatment in myeloma cell lines and CD138(+) myeloma cells elicits its deleterious effects through inhibition of translation and induction of autophagy.
['Cervantes-Gomez|Fabiola|F|', 'Chen|Lisa S|LS|', 'Orlowski|Robert Z|RZ|', 'Gandhi|Varsha|V|']
D000818:Animals D001343:Autophagy D016923:Cell Death D048708:Cell Growth Processes D045744:Cell Line, Tumor D006801:Humans D007093:Imidazoles D051379:Mice D009101:Multiple Myeloma D047428:Protein Kinase Inhibitors D051573:Proto-Oncogene Proteins c-pim-1 D011724:Pyridazines
Pim kinase inhibitor SGI-1776 Multiple myeloma Cell death Autophagy