title: Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance.
abstract: The BCR/ABL kinase has been targeted for the treatment of chronic myelogenous leukemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML and Ph+ acute lymphoblastic leukemia (ALL) are often resistant. In particular, mutation of the T315 residue in the bcr/abl activation loop renders cells highly resistant to imatinib and to second-generation kinase inhibitors such as BMS-354825 or AMN107. Adaphostin is a tyrphostin that was originally intended to inhibit the BCR/ABL kinase by competing with its peptide substrates. Recent findings have in addition implicated reactive oxygen species (ROS) in the cytotoxic mechanism of adaphostin. In view of this unique mode of action, we examined the effects of adaphostin on numerous imatinib-resistant leukemia models, including imatinib-resistant CML and Ph+ ALL cell lines, cells harboring point mutations in BCR/ABL, and specimens from imatinib-resistant CML patients, using assays for intracellular ROS, apoptosis, and clonogenicity. Every model of imatinib resistance examined remained fully sensitive to adaphostin-induced cell death. Collectively, these data suggest that ROS generation by adaphostin overcomes even the most potent imatinib resistance in CML and Ph+ ALL.
authors.affiliation: Department of Pediatrics Research, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. jchandra@mdanderson.org
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
authors.forename: Jeannette
authors.initials: J
authors.lastname: Tracy
authors.forename: David
authors.initials: D
authors.lastname: Loegering
authors.forename: Karen
authors.initials: K
authors.lastname: Flatten
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Miloslav
authors.initials: M
authors.lastname: Beran
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gorre
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Nicholas
authors.initials: N
authors.lastname: Donato
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Charles
authors.initials: C
authors.lastname: Sawyers
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
authors.forename: Judith
authors.initials: J
authors.lastname: Karp
authors.forename: Edward
authors.initials: E
authors.lastname: Sausville
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides; D045744:Cell Line, Tumor; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species
chemical_list: D001549:Benzamides; D006873:Hydroquinones; C404397:NSC 680410; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000218:Adamantane