Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity.
Bcr-Abl is one of the most potent antiapoptotic molecules and is the tyrosine-kinase implicated in Philadelphia (Ph) chromosome-positive leukemia. It is still obscure how Bcr-Abl provides the leukemic cell a strong resistance to chemotherapeutic drugs. A rational drug development produced a specific inhibitor of the catalytic activity of Bcr-Abl called STI571. This drug was shown to eliminate Bcr-Abl-positive cells both in vitro and in vivo, although resistant cells may appear in culture and relapse occurs in some patients. In the study described here, Bcr-Abl-positive cells treated with tyrosine-kinase inhibitors such as herbimycin A, genistein or STI571 lost their phosphotyrosine-containing proteins, but were still extremely resistant to apoptosis. Therefore, in the absence of tyrosine-kinase activity, Bcr-Abl-positive cells continue to signal biochemically to prevent apoptosis induced by chemotherapeutic drugs. We propose that secondary antiapoptotic signals are entirely responsible for the resistance of Bcr-Abl-positive cells. Precise determination of such signals and rational drug development against them should improve the means to combat Ph chromosome-positive leukemia.
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Brazil.
A E B
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Bueno-da-Silva
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Brumatti
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Russo
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Green
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Amarante-Mendes
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D016227:Benzoquinones; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D047029:Lactams, Macrocyclic; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D010879:Piperazines; D011743:Pyrimidines; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D000068877:Imatinib Mesylate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D020169:Caspases