Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia
文献类型：期刊论文
| 作者 | Zhang, Xin3; Jia, Deyong3; Ao, Junping4; Liu, Huijuan3; Zang, Yi5 ; Azam, Mohammad6,7,8; Habib, Samy L.1,9; Li, Jia5; Ruan, Xinsen3; Jia, Hao3
|
| 刊名 | ONCOTARGET
 |
| 出版日期 | 2016-10-25 |
| 卷号 | 7期号:43页码:69945-69960 |
| ISSN号 | 1949-2553 |
| 关键词 | Bisindolylmaleimide IX BCR-ABL chronic myeloid leukemia (CML) |
| DOI | 10.18632/oncotarget.11566 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | CHRONIC MYELOID-LEUKEMIA ; PROTEIN-KINASE-C ; DOUBLE-STRAND BREAKS ; DNA-DAMAGE RESPONSE ; CELL-DEATH ; STEM/PROGENITOR CELLS ; IMATINIB RESISTANCE ; CDC25 PHOSPHATASES ; TOPOISOMERASE-I ; CANCER-THERAPY |
| 资助项目 | Natural Science Foundation of China[81130039] ; Natural Science Foundation of China[81121001] ; Ministry of Science and Technology of China (The National Key Scientific Program)[2012CB966901] ; Ministry of Science and Technology of China (The National Key Scientific Program)[2014CB942900] ; Shanghai Zhangjiang Stem Cell Research Project[ZJ2014-ZD-002] |
| WOS研究方向 | Oncology ; Cell Biology |
| 语种 | 英语 |
| 出版者 | IMPACT JOURNALS LLC |
| WOS记录号 | WOS:000387448300065 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275847]  |
| 专题 | 国家新药筛选中心 药物安全性评价中心 |
| 通讯作者 | Li, Baojie |
| 作者单位 | 1.Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA; 2.Tongji Univ, Shanghai East Hosp, Translat Med Ctr Stem Cell Therapy, Sch Med, Shanghai, Peoples R China 3.Shanghai Jiao Tong Univ, Minist Educ, Key Lab Genet Dev & Neuropsychiat Disorders, BioX Inst, Shanghai, Peoples R China; 4.Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Shanghai Canc Inst, Renji Hosp,Sch Med, Shanghai, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Natl Ctr Drug Screening, Shanghai, Peoples R China; 6.Cincinnati Childrens Hosp & Med Ctr, Canc & Blood Dis Inst, Div Pathol, Cincinnati, OH USA; 7.Cincinnati Childrens Hosp & Med Ctr, Canc & Blood Dis Inst, Div Hematol, Cincinnati, OH USA; 8.Cincinnati Childrens Hosp & Med Ctr, Canc & Blood Dis Inst, Div Canc Biol, Cincinnati, OH USA; 9.Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA; 10.Natl Univ Singapore, Dept Biochem, Singapore, Singapore; |
| 推荐引用方式 GB/T 7714 | Zhang, Xin,Jia, Deyong,Ao, Junping,et al. Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia[J]. ONCOTARGET,2016,7(43):69945-69960. |
| APA | Zhang, Xin.,Jia, Deyong.,Ao, Junping.,Liu, Huijuan.,Zang, Yi.,...&Li, Baojie.(2016).Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia.ONCOTARGET,7(43),69945-69960. |
| MLA | Zhang, Xin,et al."Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia".ONCOTARGET 7.43(2016):69945-69960. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。