title: Spautin-1, a novel autophagy inhibitor, enhances imatinib-induced apoptosis in chronic myeloid leukemia.
abstract: Imatinib mesylate (IM), a targeted competitive inhibitor of the BCR-ABL tyrosine kinase, has revolutionized the clinical treatment of chronic myeloid leukemia (CML). However, resistance and intolerance are still a challenge in the treatment of CML. Autophagy has been proposed to play a role in IM resistance. To investigate the anti-leukemic activity of specific and potent autophagy inhibitor-1 (spautin-1) in CML, we detected its synergistic effect with IM in K562 and CML cells. Our results showed that spautin-1 markedly inhibited IM-induced autophagy in CML cells by downregulating Beclin-1. Spautin-1 enhanced IM-induced CML cell apoptosis by reducing the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2. We further demonstrated that the pro-apoptotic activity of spautin-1 was associated with activation of GSK3β, an important downstream effector of PI3K/AKT. The findings indicate that the autophagy inhibitor spautin-1 enhances IM-induced apoptosis by inactivating PI3K/AKT and activating downstream GSK3β, leading to downregulation of Mcl-1 and Bcl-2, which represents a promising approach to improve the efficacy of IM in the treatment of patients with CML.
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Shao
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Su
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Yining
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Chuxian
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001549:Benzamides / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D001549:Benzamides; D001596:Benzylamines; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010879:Piperazines; D011743:Pyrimidines; D011799:Quinazolines; C000591235:spautin-1; D000068877:Imatinib Mesylate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3