Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity.
As more and more effective targeted therapeutics have been developed to treat adults with cancer, it is of critical importance to devise appropriate in vitro experimental models to study their use in pediatric patients. Acute lymphoblastic leukemia (ALL) with Bcr-Abl translocation is one of the most difficult to treat and deadly diseases in children. The targeted kinase inhibitor imatinib mesylate has been shown to induce an initial response but resistance often develops. Recently, the geldanamycin family of antibiotics has been found to induce apoptosis in many malignant cells, including adult CML and AML. We describe experiments in which 17-allylamino-17-demethoxygeldanamycin (17-AAG) was evaluated in the context of Bcr-Abl and resistance to imatinib mesylate. Pediatric ALL cell lines with varying Bcr-Abl status and imatinib mesylate sensitivity were generated and their growth inhibition by 17-AAG was studied in vitro. Western blots were used to follow the changes in proteins that correlate with cell survival. Results show that apoptosis was induced in all lines with an increased 50% inhibitory concentration (IC50) for Bcr-Abl positive but imatinib mesylate-resistant cells. Addition of 17-AAG greatly increased imatinib sensitivity in vitro. A decrease in p53, survivin, Her2/neu, and WT1 was seen in cells that expressed these proteins. With some notable exceptions, when combined with 17-AAG, the IC50 of most of the common chemotherapeutic agents decreased. We describe an experimental approach to investigate the complex interaction between Bcr-Abl status, imatinib mesylate sensitivity, and 17-AAG in pediatric ALL. Information from such an approach will provide means to devise combined treatment approaches and to follow their effectiveness in vitro.
Hawkins
Lindsay M
LM
Center for Experimental and Molecular Therapeutics for Childhood Cancers, Southern Alberta Children's Cancer Program, Alberta Children's Hospital, Calgary, Alberta T2T 5C7, Canada.
Jayanthan
Aarthi A
AA
Narendran
Aru
A
D000328:Adult; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D016227:Benzoquinones; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D047029:Lactams, Macrocyclic; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001549:Benzamides; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017828:Rifabutin; C112765:tanespimycin; D000068877:Imatinib Mesylate