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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Claudia Stolz - , University Hospital Essen (Author)
  • Georg Hess - , Institute of Fluid Power (Author)
  • Patricia S Hähnel - (Author)
  • Florian Grabellus - (Author)
  • Sandra Hoffarth - (Author)
  • Kurt W Schmid - (Author)
  • Martin Schuler - (Author)

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.

Details

Original languageEnglish
Pages (from-to)3312-21
Number of pages10
JournalBlood
Volume112
Issue number8
Publication statusPublished - 15 Oct 2008
Peer-reviewedYes

External IDs

Scopus 54049111866
ORCID /0000-0002-5247-908X/work/142241946

Keywords

Keywords

  • 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, 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