Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia
| Autor: | Jia Li, Hao Jia, Xin Zhang, Xinsen Ruan, Junping Ao, Baojie Li, Xueying Wang, Samy L. Habib, Mohammad Azam, Yi Zang, Deyong Jia, Huijuan Liu |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Proto-Oncogene Proteins B-raf 0301 basic medicine Oncology Gerontology medicine.medical_specialty Bisindolylmaleimide Indoles Topoisomerase Inhibitors Fusion Proteins bcr-abl Drug resistance Maleimides Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Internal medicine medicine Animals Humans chronic myeloid leukemia (CML) neoplasms BCR-ABL Bisindolylmaleimide IX Mice Inbred BALB C Hematology biology business.industry Topoisomerase Myeloid leukemia Cancer Cell Cycle Checkpoints HCT116 Cells Oncogene Addiction medicine.disease Mice Inbred C57BL Leukemia 030104 developmental biology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein K562 Cells business Research Paper DNA Damage |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Xin Zhang 1, * , Deyong Jia 1, * , Junping Ao 2, * , Huijuan Liu 1 , Yi Zang 3 , Mohammad Azam 4 , Samy L. Habib 5 , Jia Li 3 , Xinsen Ruan 1 , Hao Jia 1 , Xueying Wang 6 , Baojie Li 1, 7 1 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China 3 National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 4 Divisions of Pathology, Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH, USA 5 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 6 Department of Biochemistry, National University of Singapore, Singapore 7 Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China * These authors have contributed equally to this work Correspondence to: Baojie Li, email: libj@sjtu.edu.cn Keywords: Bisindolylmaleimide IX, BCR-ABL, chronic myeloid leukemia (CML) Received: June 08, 2015 Accepted: August 08, 2016 Published: August 24, 2016 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. |
| Databáze: | OpenAIRE |
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