title: Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism.
abstract: Mutation of Bcr-Abl is an important mechanism by which chronic myelogenous leukemia (CML) cells become resistant to Gleevec. The T315I mutation is clinically significant since CML cells harboring this mutation are insensitive to Gleevec and other Bcr-Abl-targeted drugs. Identification of new agents capable of effectively killing CML cells with T315I mutation would have important therapeutic implications in Gleevec-resistant CML. Here, we showed that beta-phenylethyl isothiocyanate (PEITC), a natural compound found in vegetables, is effective in killing CML cells expressing T315I BCR-ABL. Treatment of leukemia cell lines harboring wild-type or mutant Bcr-Abl with 10 microM PEITC resulted in an elevated ROS stress and a redox-mediated degradation of the BCR-ABL protein, leading to massive death of the leukemia cells. Antioxidant NAC attenuated the PEITC-induced oxidative stress in CML cells and prevented the degradation of BCR-ABL, caspase-3 activation and cell death. We further showed that the ROS-induced degradation of BCR-ABL was mediated partially by caspase-3 and the proteasome pathway. The ability of PEITC to effectively kill T315I-positive CML cells was further confirmed using primary leukemia cells isolated from CML patients. Our results suggest that PEITC is a promising compound capable of killing Gleevec-resistant CML cells through a ROS-mediated mechanism and warrants further investigations.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Trachootham
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Carew
authors.forename: F J
authors.initials: FJ
authors.lastname: Giles
authors.forename: M J
authors.initials: MJ
authors.lastname: Keating
authors.forename: R B
authors.initials: RB
authors.lastname: Arlinghaus
authors.forename: P
authors.initials: P
authors.lastname: Huang
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D017879:Isothiocyanates / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology*; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D001549:Benzamides; D017879:Isothiocyanates; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C058305:phenethyl isothiocyanate; D000068877:Imatinib Mesylate; D000444:Aldehyde Dehydrogenase; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D053148:Caspase 3; D005978:Glutathione