Propranolol Enhances The Sensitivity Of AML To The MCL-1 Inhibitor S63845 By Blocking β2-AR

Background: The anti-apoptotic protein MCL-1 is of great significance to the occurrence and development of acute myeloid leukemia(AML).Compared with the anti-apoptotic proteins BCL-2 and BCL-XL,AML cells are more dependent on MCL-1 for survival.MCL-1 protein may have more potential in the treatment of AML.Stress hormones can promote the resistance of tumor cells to multiple drugs through β2-adrenergic receptors(β2-AR),whether stress hormones can promote the resistance of AML cells to the MCL-1 inhibitor S63845 and the β-AR blocker propranolol can enhance S63845 sensitivity remains to be investigated.Methods: 1)Through CCK8 and Western blot experiments,to explore isoproterenol(ISO),and β-AR blocker propranolol,β1-AR blocker atenolol,β2-AR blocker ICI-118551 to AML cell viability,S63845 sensitivity and BCL-2 family protein expression;2)CCK8,flow detection of cell apoptosis,Construction of S63845 resistant cell line,nude mice Subcutaneous tumor formation and other experiments to determine whether propranolol can enhance the sensitivity of S63845 in vitro and in vivo;3)Western blot detection of the effects of propranolol and S63845 alone or combination on the expression of BCL-2 family proteins,and MCL-1 stable interference cell line was established,and the mechanism of propranolol enhancing S63845 sensitivity was preliminarily explored.Results: 1)ISO can up-regulate the expression of MCL-1 protein,promote the proliferation of AML cells and S63845 resistance;2)Both propranolol and ICI-118551 can down-regulate the expression of MCL-1protein,inhibit the viability of AML cells and enhance the sensitivity of S63845;3)Propranolol and S63845 have synergistic anti-AML effects in vitro and in vivo;4)S63845 significantly up-regulated the expression of MCL-1 protein,and propranolol could significantly down-regulate the expression of MCL-1 protein;knocking down MCL-1 could increase the sensitivity of S63845.Conclusion: Stress hormones can promote S63845 resistance,and propranolol down-regulates the expression of MCL-1 protein by blockingβ2-AR,enhancing S63845 sensitivity in vitro and in vivo.