Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells.
Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromosome-positive leukemia, but resistance develops in all phases of the disease. Bcr/Abl point mutations and other alterations reduce the kinase inhibitory activity of imatinib mesylate; thus, agents that target Bcr/Abl through unique mechanisms may be needed. Here we describe the activity of WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells. Loss of Bcr/Abl protein correlated with the onset of apoptosis and reduced phosphorylation of Bcr/Abl substrates. WP1130 did not affect Hsp90/Hsp70 ratios within the cells and did not require the participation of the proteasomal pathway for loss of Bcr/Abl protein. WP1130 was more effective in reducing leukemic versus normal hematopoietic colony formation and strongly inhibited colony formation of cells derived from patients with T315I mutant Bcr/Abl-expressing CML in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T315I mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML.
Bartholomeusz
Geoffrey A
GA
Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Talpaz
Moshe
M
Kapuria
Vaibhav
V
Kong
Ling Yuan
LY
Wang
Shimei
S
Estrov
Zeev
Z
Priebe
Waldemar
W
Wu
Ji
J
Donato
Nicholas J
NJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003487:Cyanoacrylates; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
D001549:Benzamides; D003487:Cyanoacrylates; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C519751:degrasyn; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl