Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab

Br J Haematol. 2006 Sep;134(5):475-84. doi: 10.1111/j.1365-2141.2006.06210.x.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a common lymphoma entity. Although a significant amount of DLBCL patients can be cured with modern chemotherapeutic regimens, a substantial proportion of patients die because of progressive disease. Therefore, new therapeutic strategies are clearly needed. Inhibitors of mTOR [mammalian target of rapamycin (Rap)] represent a new class of antiproliferative drugs with applications as immunosuppressive and anticancer agents. Extensive safety data exist on the mTOR inhibitor RAD001, which is already approved as an immunosuppressant in organ transplant recipients. Rap and RAD001 inhibited cell cycle progression in DLBCL cells by inducing a G1 arrest without inducing apoptosis. Phosphorylation of the main targets of mTOR, p70 s6 kinase and 4-EBP-1 was reduced in cells cultured in the presence of RAD001. Cell cycle arrest was accompanied by reduced phosphorylation of the retinoblastoma protein (RB) as well as reduced expression of cyclin D3 and A in all cell lines. Although the effect of the chemotherapeutic agent vincristine (vin) was not enhanced by RAD001, rituximab-induced cytotoxicity was augmented in the rituximab-sensitive cell lines. mTOR inhibition is a promising therapeutic strategy in DLBCL by inducing a G1 arrest and augments rituximab-induced cytotoxicity. Therefore, combination of these drugs might be an interesting new therapeutic approach in DLBCL patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Annexin A5 / analysis
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Murine-Derived
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Electrophoretic Mobility Shift Assay
  • Everolimus
  • Flow Cytometry
  • G1 Phase
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • In Situ Nick-End Labeling
  • Lymphoma, B-Cell / drug therapy
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / metabolism
  • Lymphoma, Non-Hodgkin / pathology
  • Oncogene Protein v-akt / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Kinases / metabolism*
  • Retinoblastoma Protein / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Rituximab
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases

Substances

  • Adaptor Proteins, Signal Transducing
  • Annexin A5
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Immunosuppressive Agents
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Retinoblastoma Protein
  • Rituximab
  • Everolimus
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Oncogene Protein v-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Sirolimus