Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines.
Imatinib mesylate is a selective inhibitor of the oncogenic tyrosine kinase, Bcr-Abl, and is widely used as a first-line treatment for chronic myeloid leukaemia (CML). Prolonged monotherapy is frequently associated with patients becoming refractory to imatinib. Therefore, there is considerable interest in small molecule inhibitors which may be used either as replacements or as adjuncts to existing imatinib therapy. For this purpose, it is most likely that drugs which do not share imatinib's mechanism of action will be most valuable. We compared two such compounds with different modes of action, adaphostin and 17-allylamino-17-demethoxygeldanamycin (17-AAG), for their cytotoxic effect and ability to induce the downregulation of cellular proteins in a murine haemopoietic cell line transformed with human p210(Bcr-Abl), and two subclones resistant to imatinib owing to an Abl-kinase domain mutation (E255K) or amplification of the BCR-ABL gene, respectively. We found that, whereas 17-AAG selectively killed Bcr-Abl-positive cells and inhibited proteins dependent on heat-shock protein 90 for their stability (p210(Bcr-Abl) and Akt), adaphostin induced the downregulation of multiple cell-signalling proteins (p210(Bcr-Abl), Akt, Bcr, Abl and STAT5a) and was cytotoxic to both Bcr-Abl-positive and -negative cells. We suggest that both compounds may prove useful in the treatment of CML but caution that undesirable side-effects may result from the inhibition of multiple cell signalling proteins.
Barnes
D J
DJ
1Department of Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
De
S
S
van Hensbergen
P
P
Moravcsik
E
E
Melo
J V
JV
D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D016227:Benzoquinones / Q000009:adverse effects / Q000494:pharmacology*; D002461:Cell Line, Transformed / Q000187:drug effects / Q000201:enzymology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D002999:Clone Cells / Q000187:drug effects / Q000201:enzymology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016313:Genes, abl; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006873:Hydroquinones / Q000009:adverse effects / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D047029:Lactams, Macrocyclic / Q000009:adverse effects / Q000494:pharmacology*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D051562:Proto-Oncogene Proteins c-bcr / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D014162:Transfection
D000970:Antineoplastic Agents; D001549:Benzamides; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D006873:Hydroquinones; D047029:Lactams, Macrocyclic; D050505:Mutant Proteins; C404397:NSC 680410; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C112765:tanespimycin; D000068877:Imatinib Mesylate; D006861:Hydrogen Peroxide; D016044:Fusion Proteins, bcr-abl; C514862:Akt1 protein, mouse; C496614:Bcr protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051562:Proto-Oncogene Proteins c-bcr; D000218:Adamantane