全反式维甲酸与卡非佐米通过ROS/Drp1/线粒体轴协同诱导急性髓系白血病细胞凋亡OA

Objective To investigate the synergistic effect of all-trans retinoic acid(ATRA)combined with the proteasome inhibitor carfilzomib(CFZ)in the treatment of acute myeloid leukemia(AML)and to elucidate the underlying molecular mechanisms.Methods AML cell lines MV-4-11 and U937 were used.Cell viability was as-sessed by CCK-8 assay.Intracellular reactive oxygen species(ROS)levels and apoptosis were measured by flow cytometry.The mitochondrial membrane potential detection was used to assess mitochondrial function.The pro-tein expression of apoptosis-related proteins was analyzed using western blotting.Results The combination of AT-RA/CFZ synergistically inhibited AML cell proliferation and significantly induced apoptosis,accompanied by degradation of PARP,cleavage/activation of Caspase-3 and Caspase-9.Simultaneously,it leads to the downreg-ulation of mitochondrial membrane potential.Mechanistically,the combined treatment resulted in downregulation of Mcl-1 and mitochondrial translocation of Bax,leading to the release of cytochrome c from mitochondria into the cytoplasm.Furthermore,the combined treatment of ATRA/CFZ inhibited phosphorylation of Drp1(Ser637),leading to mitochondrial translocation of Drp1.Pretreatment with Mdivi-1,a Drp1 inhibitor,attenuated ATRA/CFZ-mediated mitochondrial translocation of Drp1 and Bax,downregulation of Mcl-1,cleavage/activation of Caspase-3 and Caspase-9,as well as induction of apoptosis.Additionally,combined treatment with ATRA/CFZ markedly elevated ROS levels.Pretreatment with NAC,a ROS inhibitor,attenuated ATRA/CFZ-mediated Drp1 inactivation and its mitochondrial translocation,cytochrome c release,and apoptosis.Conclusion The combina-tion of ATRA/CFZ induces robust oxidative stress,leading to Drp1(Ser637)dephosphorylation and its translo-cation to the mitochondria,and culminating in the cleavage/activation of Caspase-3 and Caspase-9,resulting in apoptosis in AML cells.