title: Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma.
abstract: 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.
authors.affiliation: Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Qing
authors.affiliation: Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, 197 Rui Jin Er Road, Shanghai, China. xuzizhen@126.com.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China. drlijunmin@126.com.
authors.forename: Junmin
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D000077269:Lenalidomide; D019869:Phosphatidylinositol 3-Kinases; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D013792:Thalidomide; C546842:MTOR protein, human; C531198:dactolisib
keywords: Apoptosis; Cell cycle; Diffuse large B cell lymphoma; Lenalidomide; NF-κB; PI3K/mTOR inhibitor