Synergistic Effect of IGF1-R Inhibitor AEW541 on Imatinib Indu-cing SUP-B15 Cell Death
10.19746/j.cnki.issn1009-2137.2024.06.011
- VernacularTitle:IGF1-R抑制剂AEW541对伊马替尼杀伤SUP-B15细胞的增效作用
- Author:
Cong-Yue WANG
1
;
Wen-Wen ZHANG
;
Li NIAN
;
Xu CAO
;
Jing-Jing XI
;
Wen-Tong GUO
;
Chong CHEN
Author Information
1. 徐州医科大学血液病研究所
- Keywords:
drug tolerance;
apoptosis;
Ph+acute lymphoblastic leukemia;
imatinib;
AEW541
- From:
Journal of Experimental Hematology
2024;32(6):1704-1710
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore whether Ph+acute lymphoblastic leukemia (ALL)cell line SUP-B15 treated with imatinib occurs a tolerant status charactered by cell proliferation suppression but apoptotic resistance,then evaluate whether IGF1-R inhibitor AEW541 can break this tolerance,and further explain its mechanisms.Methods:SUP-B15 cells were treated with different concentrations of imatinib or AEW541.Cell proliferation was assayed by Deep Blue,and apoptotic cells were determined by Annexin V/7-AAD staining.Apoptotic rate was measured by flow cytometry after co-treatment of imatinib and AEW541.Western blot was used to evaluate ABL downstream signals,including the phosphorylation of STAT5,ERK1/2,and AKT,as well as to detect cleaved caspase-3 and PARP1,the molecular signatures of apoptosis.Furthermore,an inhibitor of STAT5 or MEK-ERK1/2 was used to confirm the key mechanism of the combination of imatinib and AEW541 induced SUP-B15 cell apoptosis.Results:Imatinib monotherapy effectively suppressed the proliferation of SUP-B15 cells,but did not induce significant increase of apoptotic rate,leading to occurrence of tolerant status.AEW541 monotherapy did not dramatically affect the proliferation and apoptosis of SUP-B15 cells,but significantly increased apoptotic rate of SUP-B15 cells and cleavage of caspase-3 and PARP1 when combined with imatinib simultaneously. A combination of imatinib and AEW541 reduced STAT5 and ERK1/2 phosphorylation as compared with imatinib monotherapy in SUP-B15 cells,but had no impact on AKT phosphorylation.Apoptosis could be induced by STAT5 inhibitor AC-4-130,but not by MEK-ERK1/2 inhibitor trametinib in SUP-B15 cells.Conclusion:SUP-B15 cells treated with imatinib can establish drug tolerance.IGF1-R inhibitor AEW541 can further reduce STAT5 activation,thereby boosting the effect of apoptotic induction of imatinib on SUP-B15 cells.This research may provide a new idear to overcome imatinib tolerance.
