title: Cryptotanshinone acts synergistically with imatinib to induce apoptosis of human chronic myeloid leukemia cells.
abstract: Imatinib resistance has emerged as a significant clinical problem in chronic myeloid leukemia (CML) treatment. In this study, we investigated the effect and mechanism of combination treatment with imatinib and cryptotanshinone (CPT) in CML cells. Cotreatment with imatinib and CPT showed a significant synergistic killing effect in both imatinib sensitive and resistant CML cell lines, as well as primary CML cells. Furthermore, combination treatment induced apoptosis significantly, as indicated by increases in apoptotic cell fraction and activities of proapoptotic proteins. Subsequent studies revealed that CPT significantly inhibited Bcr/Abl protein expression, as well as phosphorylation expression levels of signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E (eIF4E), which are critical mediators of Bcr/Abl transformation. Furthermore, CPT in combination with imatinib dramatically decreased the activity of the Bcr/Abl pathway in both K562 and K562-R cells. Our results demonstrated that CPT increased imatinib-induced apoptosis in a Bcr/Abl dependent manner, suggesting a novel strategy for the treatment of CML.
authors.affiliation: Zhejiang Hospital of Traditional Chinese Medicine.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Ge
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xu
authors.forename: Qun
authors.initials: Q
authors.lastname: Dai
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.forename: Rubin
authors.initials: R
authors.lastname: Cheng
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004365:Drugs, Chinese Herbal; D039561:Eukaryotic Initiation Factor-4E; D010616:Phenanthrenes; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C037886:cryptotanshinone; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D058570:TOR Serine-Threonine Kinases
keywords: Bcr/Abl pathway; CPT; imatinib resistance; synergism