The rho-kinase inhibitors Y-27632 and fasudil act synergistically with imatinib to inhibit the expansion of ex vivo CD34(+) CML progenitor cells.
Evidence from cell line-based studies indicates that rho-kinase may play a role in the leukaemic transformation of human cells mediated by the BCR/ABL tyrosine kinase, manifest clinically as chronic myeloid leukaemia (CML). We therefore employed two separate inhibitors, Y-27632 and fasudil, to inhibit the activity of rho-kinase against ex vivo CD34(+) cells collected from patients with CML. We compared the effects of rho-kinase inhibition in those cells with the effects of direct inhibition of BCR/ABL using the specific inhibitor imatinib. We found that inhibition of rho-kinase inhibited the effective proliferation, and reduced survival of CML progenitor cells. When combined with imatinib, rho-kinase inhibition added to the anti-proliferative and pro-apoptotic effects of the BCR/ABL inhibitor. Our studies may indicate therapeutic benefit in some cases for the combination of rho-kinase inhibitors with imatinib.
Burthem
J
J
Division of Laboratory and Regenerative Medicine, Stopford Building, Manchester, UK. john.burthem@cmmc.nhs.uk
Rees-Unwin
K
K
Mottram
R
R
Adams
J
J
Lucas
G S
GS
Spooncer
E
E
Whetton
A D
AD
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000577:Amides / Q000627:therapeutic use*; D018952:Antigens, CD34 / Q000378:metabolism*; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013234:Stem Cells; D014407:Tumor Cells, Cultured / Q000187:drug effects; D054460:rho-Associated Kinases
D000577:Amides; D018952:Antigens, CD34; D001549:Benzamides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil