The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells.

Abstract

The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the extracellular signal-regulated kinase (ERK) pathway, downstream of BCR-ABL, by treating CD34+ CML stem/progenitor cells with a highly selective adenosine triphosphate (ATP) non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared with BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, -8 and -9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant-negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease.

• Authors: F Pellicano, P Simara, A Sinclair, G V Helgason, M Copland, S Grant, T L Holyoake
• Journal: Leukemia (Leukemia) Vol. 25 Issue 7 Pg. 1159-67 (Jul 2011) ISSN: 1476-5551 [Electronic] England
• PMID: 21483442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Antigens, CD34
• Benzamides
• Enzyme Inhibitors
• Imidazoles
• Neoplasm Proteins
• Recombinant Fusion Proteins
• Benzodiazepines
• Farnesyltranstransferase
• MAP Kinase Kinase Kinases
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• Oncogene Protein p21(ras)
• 7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine

Topics

• Antigens, CD34 (analysis)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Benzodiazepines (pharmacology)
• Blast Crisis (enzymology, pathology)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Farnesyltranstransferase (antagonists & inhibitors)
• Genes, Dominant
• Genes, ras
• Hematopoietic Stem Cells (drug effects, enzymology)
• Humans
• Imidazoles (pharmacology)
• K562 Cells (drug effects, enzymology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (enzymology, pathology)
• Leukemia, Myeloid, Chronic-Phase (enzymology, pathology)
• MAP Kinase Kinase 1 (genetics)
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Neoplasm Proteins (antagonists & inhibitors)
• Neoplastic Stem Cells (drug effects, enzymology)
• Oncogene Protein p21(ras) (genetics)
• Recombinant Fusion Proteins (genetics)
• Tumor Cells, Cultured (drug effects, enzymology)