Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma

Background: activated b cell-like subtype of diffuse large b cell lymphoma (abc-dlbcl) presents aggressive clinical courses and poor prognosis. targeting key pathways may raise the possibility of improving clinical outcomes. methods: the synergetic effects were assessed by cck-8 assay and measured by isobologram analysis. the nvp-bez235 and lenalidomide cytotoxicity were measured by flow cytometry,western blot and si-rna transfection. the combined treatment inducing tumor regression in vivo was performed in nude mice of oci-ly10 xenograft mouse model. results: low dose of two agents represented significant inhibition of proliferation with ci value < 1. nvp-bez235 combined with lenalidomide remarkably increased apoptosis through intrinsic pathway by upregulating bim,bax and downregulating bcl-xl. akt,especially nf-κb,played an important role in the synergetic effects. cotreatment also induced the cell cycle to be arrested in g0/g1 phase,and decreased s phase by increasing p21 expression,downregulating cyclina and diminishing cdk2 phosphorylation in su-dhl2 and oci-ly3 but not in oci-ly10. mice treated with nvp-bez235/lenalidomide represented obvious tumor growth regression and prolonged overall survival. conclusions: our findings demonstrated the synergistic effect of low dose of nvp-bez235 and lenalidomide in abc-dlbcl,the underlying mechanism may be multifunctional,involving apoptosis,akt and nf-κb inactivation and cell cycle arrest. cotreatment was also effective in vivo. these data pave the way for potential treatment of abc-dlbcl with combination of nvp-bez235 and lenalidomide. © 2016 jin et al.