title: Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia.
abstract: Chronic myeloid leukemia (CML) treatment with BCR-ABL inhibitors is often hampered by development of drug resistance. In a screen for novel chemotherapeutic drug candidates with genotoxic activity, we identified a bisindolylmaleimide derivative, IX, as a small molecule compound with therapeutic potential against CML including drug-resistant CML. We show that Bisindolylmaleimide IX inhibits DNA topoisomerase, generates DNA breaks, activates the Atm-p53 and Atm-Chk2 pathways, and induces cell cycle arrest and cell death. Interestingly, Bisindolylmaleimide IX is highly effective in targeting cells positive for BCR-ABL. BCR-ABL positive cells display enhanced DNA damage and increased cell cycle arrest in response to Bisindolylmaleimide IX due to decreased expression of topoisomerases. Cells positive for BCR-ABL or drug-resistant T315I BCR-ABL also display increased cytotoxicity since Bisindolylmaleimide IX inhibits B-Raf and the downstream oncogene addiction pathway. Mouse cancer model experiments showed that Bisindolylmaleimide IX, at doses that show little side effect, was effective in treating leukemia-like disorders induced by BCR-ABL or T315I BCR-ABL, and prolonged the lifespan of these model mice. Thus, Bisindolylmaleimide IX presents a novel drug candidate to treat drug-resistant CML via activating BCR-ABL-dependent genotoxic stress response and inhibiting the oncogene addiction pathway activated by BCR-ABL.
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors: Xin
authors: X
authors: Zhang
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors: Deyong
authors: D
authors: Jia
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors: Junping
authors: J
authors: Ao
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors: Huijuan
authors: H
authors: Liu
authors: National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Yi
authors: Y
authors: Zang
authors: Divisions of Pathology, Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, USA.
authors: Mohammad
authors: M
authors: Azam
authors: South Texas Veterans Health Care System and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Samy L
authors: SL
authors: Habib
authors: National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Jia
authors: J
authors: Li
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors: Xinsen
authors: X
authors: Ruan
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors: Hao
authors: H
authors: Jia
authors: Department of Biochemistry, National University of Singapore, Singapore.
authors: Xueying
authors: X
authors: Wang
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.|Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Baojie
authors: B
authors: Li
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology; D059003:Topoisomerase Inhibitors / Q000494:pharmacology
chemical_list: D007211:Indoles; D008301:Maleimides; D059003:Topoisomerase Inhibitors; C467001:bisindolylmaleimide IX; D016044:Fusion Proteins, bcr-abl; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BCR-ABL; Bisindolylmaleimide IX; chronic myeloid leukemia (CML)