The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia  

作　　者：Lan DENG Ling JIANG Xiang-hua LIN Kuo-Fu TSENG Yuan LIU Xing ZHANG Rui-hong DONG Zhi-gang LU Xiu-ju WANG 

机构地区：[1]Department of Hematology/Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China [2]Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 501282, China [3]Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China [4]Biophysics Department of Oregon State University, ALS-2139 Corvallis, OR 97330, USA

出　　处：《Acta Pharmacologica Sinica》2017年第3期382-391,共10页中国药理学报（英文版）

基　　金：Acknowledgements This work was supported by grants from the Natural Science Foundation of Guangdong Province, China （No S2012010008748 and S2013010014715）.

摘　　要：Aberrant activation of the PI3K/Akt/mTOR pathway contributes to the proliferation of malignant cells, and may confer resistance to chemotherapy in various malignancies, including acute myeloid leukemia （AML）. Chemoresistance is the major reason for relapse in AML. RADO01 （everolimus） has been used at dl and d7 of an induction chemotherapy regimen for AML, which has acceptable toxicity and may improve conventional chemotherapeutic treatment. Dual inhibitors of PI3K and mTOR overcome some of the intrinsic disadvantages of rapamycin and its derivatives. In this study, we evaluated the effects of BEZ235, a PI3K/mTOR dual inhibitor, on the multidrug-resistant AML cell lines HL-60/VCR and K562/ADR in vitro. BEZ235 dose-dependently inhibited the viability of HL-60/ VCR and K562/ADR cells with the ICso values of 66.69 and 71.44 nmol/L, respectively. BEZ235 （25-100 nmot/L） dose-dependently inhibited the migration of the two AML cell lines, and it also significantly sensitized the two AML cell lines to VCR and ADR. After treatment with BEZ235, the miR-1-3p levels were markedly increased in HL-60/VCR cells. Using TargetScan analysis and luciferase assays, we showed that miR-1-3p targeted BAG4, EDN1 and ABCB1, the key regulators of cell apoptosis, migration and multidrug resistance, and significantly decreased their levels in the two AML cell lines. Transfection of HL-60/VCR and K562/ADR cells with miR-1-3p-AMO to inhibit miR-1-3p could reverse the anti-proliferation effects of BEZ235. In conclusion, the PI3K/mTOR dual inhibitor BEZ235 effectively chemosensitizes AML cells via increasing miR-1-3p and subsequently down-regulating BAG4, EDN1 and ABCBI.Aberrant activation of the PI3K/Akt/mTOR pathway contributes to the proliferation of malignant cells, and may confer resistance to chemotherapy in various malignancies, including acute myeloid leukemia （AML）. Chemoresistance is the major reason for relapse in AML. RADO01 （everolimus） has been used at dl and d7 of an induction chemotherapy regimen for AML, which has acceptable toxicity and may improve conventional chemotherapeutic treatment. Dual inhibitors of PI3K and mTOR overcome some of the intrinsic disadvantages of rapamycin and its derivatives. In this study, we evaluated the effects of BEZ235, a PI3K/mTOR dual inhibitor, on the multidrug-resistant AML cell lines HL-60/VCR and K562/ADR in vitro. BEZ235 dose-dependently inhibited the viability of HL-60/ VCR and K562/ADR cells with the ICso values of 66.69 and 71.44 nmol/L, respectively. BEZ235 （25-100 nmot/L） dose-dependently inhibited the migration of the two AML cell lines, and it also significantly sensitized the two AML cell lines to VCR and ADR. After treatment with BEZ235, the miR-1-3p levels were markedly increased in HL-60/VCR cells. Using TargetScan analysis and luciferase assays, we showed that miR-1-3p targeted BAG4, EDN1 and ABCB1, the key regulators of cell apoptosis, migration and multidrug resistance, and significantly decreased their levels in the two AML cell lines. Transfection of HL-60/VCR and K562/ADR cells with miR-1-3p-AMO to inhibit miR-1-3p could reverse the anti-proliferation effects of BEZ235. In conclusion, the PI3K/mTOR dual inhibitor BEZ235 effectively chemosensitizes AML cells via increasing miR-1-3p and subsequently down-regulating BAG4, EDN1 and ABCBI.

关 键 词：acute myeloid leukemia HL-60/VCR cells K562/ADR cells CHEMORESISTANCE PI3K/mTOR BEZ235 miR-1-3p BAG4 EDN1 ABCB1 

分 类 号：R[医药卫生]