title: Blockade of the interaction between Bcr-Abl and PTB1B by small molecule SBF-1 to overcome imatinib-resistance of chronic myeloid leukemia cells.
abstract: In this study, a synthetic steroidal glycoside SBF-1 had strong and preferential antitumor effects on the human chronic myeloid leukemia (CML) cell line K562 and its imatinib-resistant form K562/G. SBF-1 induced apoptosis in both cell lines without any effect on cell cycle arrest. It also inhibited the activation of PI3K/Akt pathway members, such as PI3K and Akt, as well as downstream targets mTOR and Bcl-2. Moreover, the degradation of the Bcr-Abl protein was induced by SBF-1 in a concentration- and time-dependent manner. Using a pull-down assay, SBF-1 was found to bind to both Bcr-Abl and PTP1B and disrupted the interaction between them. SBF-1 triggered the degradation of Bcr-Abl through ubiquitination via the lysosome pathway. Taking together these findings, this study, for the first time, suggests that the blockade of the interaction between Bcr-Abl and PTP1B may be a feasible strategy for the treatment of CML, especially CML with resistance to Bcr-Abl kinase inhibitor imatinib. Our study also indicates that SBF-1 may serve as a leading compound for novel anti-CML therapeutic agents.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elgehama
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Shanwei
authors.initials: S
authors.lastname: Mi
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Jiahuang
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Academy, Shanghai, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: shenyan@nju.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002783:Cholestenones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059748:Proteolysis; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D054875:Ubiquitination
chemical_list: C581634:BCR-ABL1 fusion protein, human; D002783:Cholestenones; D047428:Protein Kinase Inhibitors; C574158:SBF-1 compound; D012503:Saponins; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Bcr-Abl; Chronic myeloid leukemia; Imatinib; PTP1B; SBF-1