Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia.

Abstract

Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-x(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment.

• Authors: Lisa S Chen, Sanjeev Redkar, Pietro Taverna, Jorge E Cortes, Varsha Gandhi
• Journal: Blood (Blood) Vol. 118 Issue 3 Pg. 693-702 (Jul 21 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21628411 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• Pim2 protein, mouse
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Pyridazines
• SGI 1776
• Pim1 protein, mouse
• Pim3 protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-pim-1

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression (drug effects)
• Humans
• Imidazoles (pharmacology)
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Myeloid Cell Leukemia Sequence 1 Protein
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Proto-Oncogene Proteins c-pim-1 (antagonists & inhibitors, metabolism)
• Pyridazines (pharmacology)
• Xenograft Model Antitumor Assays