title: Endoplasmic reticulum stress-mediated apoptosis in imatinib-resistant leukemic K562-r cells triggered by AMN107 combined with arsenic trioxide.
abstract: The first tyrosine kinase inhibitor (TKI) imatinib mesylate (imatinib) targets the kinase domain of BCR-ABL and induces apoptosis in newly diagnosed chronic myeloid leukaemia (CML). However, resistant and relapse are common problems in imatinib-treated patients. Although second-generation TKI such as AMN107 appears to improve the treatment of CML, TKI resistance and relapse are also frequently occurred in the patients. To test whether arsenic trioxide (ATO) could potentiate the efficacy of AMN107 in imatinib-resistant cells, we conducted a series of assays in TKI-resistant K562-r cells treated with AMN107 and ATO. Based on a time-course cDNA microarray analysis, we found many genes typically involved in the endoplasmic reticulum (ER) stress signalling were significantly up-regulated, implicating the occurrence of ER stress-mediated apoptosis in K562-r cells treated with the combination of ATO and AMN107. Such implication was also supported by the data showing the activation of members in the JNK pathway, which are known to be characteristic markers bridging ER-stress and apoptosis. Partial knock-down of the JNK activities alleviated the effects of apoptosis (p < 0.05) triggered by combining AMN107 with ATO. In conclusion, this study for the first time demonstrates a synergistic effect of AMN107 with ATO, allowing insights into the possible mechanisms underlying imatinib-induced resistance in CML. Our data also suggest that combination of AMN107 with ATO may represent a new strategy for the treatment of imatinib-resistant CML patients.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xia
authors.forename: Hai
authors.initials: H
authors.lastname: Fang
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Du
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D001549:Benzamides; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000077237:Arsenic Trioxide
keywords: AMN107; Chronic myeloid leukaemia; ER stress; apoptosis; arsenic trioxide; imatinib-resistant cells