Synergistic effects of p53 activation via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid leukemia blast crisis cells.

Abstract

The Bcr-Abl tyrosine kinase regulates several Bcl-2 family proteins that confer resistance to apoptosis in chronic myeloid leukemia (CML) cells. Given p53's ability to modulate the expression and activity of Bcl-2 family members, we hypothesized that targeting Bcr-Abl, Bcl-2, and p53 concomitantly could have therapeutic benefits in blast crisis (BC) CML and in quiescent CML CD34+ cells that are insensitive to tyrosine kinase inhibitors (TKI). We examined the effects of the MDM2 inhibitor nutlin3a and its combination with the dual Bcl-2 and Bcl-xL inhibitor ABT-737, and the Bcr-Abl inhibitor nilotinib on BC CML patient samples. We found that in quiescent CD34+ progenitors, p53 expression is significantly lower, and MDM2 is higher, compared to their proliferating counterparts. Treatment with nutlin3a induced apoptosis in bulk and CD34+CD38- cells, and in both proliferating and quiescent CD34+ progenitor CML cells. Nutlin3a synergized with ABT-737 and nilotinib, in part by inducing pro-apoptotic, and suppressing anti-apoptotic, Bcl-2 proteins. Nilotinib inhibited the expression of Bcl-xL and Mcl-1 in BC CML cells. These results demonstrate that p53 activation by MDM2 blockade can sensitize BC CML cells, including quiescent CD34+ cells, to Bcl-2 inhibitor- and TKI-induced apoptosis. This novel strategy could be useful in the therapy of BC CML.

• Authors: Bing Z Carter, Po Yee Mak, Duncan H Mak, Vivian R Ruvolo, Wendy Schober, Teresa McQueen, Jorge Cortes, Hagop M Kantarjian, Richard E Champlin, Marina Konopleva, Michael Andreeff
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 31 Pg. 30487-99 (Oct 13 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26431162 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Antigens, CD34
• Antineoplastic Agents
• BCL2L1 protein, human
• BCR-ABL1 fusion protein, human
• Biphenyl Compounds
• Imidazoles
• Membrane Glycoproteins
• Nitrophenols
• Piperazines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Pyrimidines
• Sulfonamides
• TP53 protein, human
• Tumor Suppressor Protein p53
• bcl-X Protein
• nutlin 3
• Imatinib Mesylate
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Fusion Proteins, bcr-abl
• CD38 protein, human
• ADP-ribosyl Cyclase 1
• nilotinib

Topics

• ADP-ribosyl Cyclase 1 (metabolism)
• Antigens, CD34 (metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Biphenyl Compounds (pharmacology)
• Blast Crisis (pathology)
• Cell Proliferation
• Enzyme Activation (physiology)
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Gene Expression Regulation, Leukemic
• Humans
• Imatinib Mesylate (pharmacology)
• Imidazoles (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (pathology)
• Membrane Glycoproteins (metabolism)
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Pyrimidines (pharmacology)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (metabolism)
• bcl-X Protein (antagonists & inhibitors)