Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis

Blood. 2008 Oct 15;112(8):3312-21. doi: 10.1182/blood-2007-11-124487. Epub 2008 Aug 8.

Abstract

The chimeric monoclonal antibody rituximab is the standard of care for patients with B-cell non-Hodgkin lymphoma (B-NHL). Rituximab mediates complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity of CD20-positive human B cells. In addition, rituximab sensitizes B-NHL cells to cytotoxic chemotherapy and has direct apoptotic and antiproliferative effects. Whereas expression of the CD20 antigen is a natural prerequisite for rituximab sensitivity, cell-autonomous factors determining the response of B-NHL to rituximab are less defined. To this end, we have studied rituximab-induced apoptosis in human B-NHL models. We find that rituximab directly triggers apoptosis via the mitochondrial pathway of caspase activation. Expression of antiapoptotic Bcl-xL confers resistance against rituximab-induced apoptosis in vitro and rituximab treatment of xenografted B-NHL in vivo. B-NHL cells insensitive to rituximab-induced apoptosis exhibit increased endogenous expression of multiple antiapoptotic Bcl-2 family proteins, or activation of phosphatidylinositol-3-kinase signaling resulting in up-regulation of Mcl-1. The former resistance pattern is overcome by treatment with the BH3-mimetic ABT-737, the latter by combining rituximab with pharmacologic phosphatidylinositol-3-kinase inhibitors. In conclusion, sensitivity of B-NHL cells to rituximab-induced apoptosis is determined at the level of mitochondria. Pharmacologic modulation of Bcl-2 family proteins or their upstream regulators is a promising strategy to overcome rituximab resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20 / biosynthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / metabolism*
  • Mice
  • Mice, SCID
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Transplantation
  • Nitrophenols / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Rituximab
  • Signal Transduction
  • Sulfonamides / pharmacology

Substances

  • ABT-737
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20
  • Antineoplastic Agents
  • Biphenyl Compounds
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Rituximab
  • Phosphatidylinositol 3-Kinases