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  2. 合肥物质科学研究院
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  4. 中科院强磁场科学中心
Simultaneous inhibition of Vps34 kinase would enhance PI3K delta inhibitor cytotoxicity in the B-cell malignancies

文献类型：期刊论文

作者Liu, Xiaochuan1,2; Wang, Aoli2,3; Liang, Xiaofei2,4; Liu, Juanjuan2,3; Zou, Fengming2,4; Chen, Cheng2,4; Zhao, Zheng2,4; Deng, Yuanxin2,3; Wu, Hong2,3; Qi, Ziping2,4
刊名ONCOTARGET
出版日期2016-08-16
卷号7期号:33页码:53515-53525
关键词Pi3k Delta Vps34 Combination Chronic Lymphatic Leukemia Acute Myeloid Leukemia
DOI10.18632/oncotarget.10650
文献子类Article
英文摘要PI3K delta has been found to be over-expressed in B-Cell-related malignancies. Despite the clinical success of the first selective PI3Kd inhibitor, CAL-101, inhibition of PI3K delta itself did not show too much cytotoxic efficacy against cancer cells. One possible reason is that PI3K delta inhibition induced autophagy that protects the cells from death. Since class III PI3K isoform PIK3C3/Vps34 participates in autophagy initiation and progression, we predicted that a PI3K delta and Vps34 dual inhibitor might improve the anti-proliferative activity observed for PI3K delta-targeted inhibitors. We discovered a highly potent ATP-competitive PI3K delta/Vps34 dual inhibitor, PI3KD/V-IN-01, which displayed 10-1500 fold selectivity over other PI3K isoforms and did not inhibit any other kinases in the kinome. In cells, PI3KD/V-IN-01 showed 30-300 fold selectivity between PI3K delta and other class I PI3K isoforms. PI3KD/V-IN-01 exhibited better anti-proliferative activity against AML, CLL and Burkitt lymphoma cell lines than known selective PI3K delta and Vps34 inhibitors. Interestingly, we observed FLT3-ITD AML cells are more sensitive to PI3KD/V-IN-01 than the FLT3 wt expressing cells. In AML cell inoculated xenograft mouse model, PI3KD/V-IN-01 exhibited dose-dependent anti-tumor growth efficacies. These results suggest that dual inhibition of PI3K delta and Vps34 might be a useful approach to improve the PI3K delta inhibitor's anti-tumor efficacy.
WOS关键词SELECTIVE INHIBITOR ; AUTOPHAGY ; 3-KINASE ; P110-DELTA ; SURVIVAL ; DYNAMIN ; PI3K
WOS研究方向Oncology ; Cell Biology
语种英语
WOS记录号WOS:000385433000068
资助机构grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; CAS/SAFEA international partnership program ; CAS/SAFEA international partnership program ; CAS/SAFEA international partnership program ; CAS/SAFEA international partnership program ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; CAS/SAFEA international partnership program ; CAS/SAFEA international partnership program ; CAS/SAFEA international partnership program ; CAS/SAFEA international partnership program ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program"
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/30137]  
专题合肥物质科学研究院_中科院强磁场科学中心
作者单位1.Univ Sci & Technol China, Dept Chem, Hefei 230036, Anhui, Peoples R China
2.Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China
3.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
4.CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China
5.Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA
6.Hefei Cosource Med Technol Co LTD, Hefei 230031, Anhui, Peoples R China
7.Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Xiaochuan,Wang, Aoli,Liang, Xiaofei,et al. Simultaneous inhibition of Vps34 kinase would enhance PI3K delta inhibitor cytotoxicity in the B-cell malignancies[J]. ONCOTARGET,2016,7(33):53515-53525.
APA Liu, Xiaochuan.,Wang, Aoli.,Liang, Xiaofei.,Liu, Juanjuan.,Zou, Fengming.,...&Liu, Qingsong.(2016).Simultaneous inhibition of Vps34 kinase would enhance PI3K delta inhibitor cytotoxicity in the B-cell malignancies.ONCOTARGET,7(33),53515-53525.
MLA Liu, Xiaochuan,et al."Simultaneous inhibition of Vps34 kinase would enhance PI3K delta inhibitor cytotoxicity in the B-cell malignancies".ONCOTARGET 7.33(2016):53515-53525.

入库方式： OAI收割

来源：合肥物质科学研究院

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