Dual inhibition of the homologous recombinational repair and the nonhomologous end-joining repair pathways in chronic lymphocytic leukemia therapy

Leuk Res. 2011 Aug;35(8):1080-6. doi: 10.1016/j.leukres.2011.01.004. Epub 2011 Feb 1.

Abstract

Resistance to chlorambucil in chronic lymphocytic leukemia (CLL) has been associated with increased DNA repair. Specifically, inhibition of either c-abl, which modulates Rad51 directed homologous recombination or DNA-PK dependent nonhomologous end joining has been shown to sensitize primary CLL lymphocytes to chlorambucil. Here we report that inhibition of c-abl can result in a compensatory increase in DNA-PK and thus inhibition of both c-abl and DNA-PK optimally sensitizes CLL lymphocytes to chlorambucil. In this paper we report a drug-induced compensatory change between two DNA repair pathways with potential therapeutic implications in CLL therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • Benzamides
  • Blotting, Western
  • Chlorambucil / pharmacology*
  • Comet Assay
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • DNA-Activated Protein Kinase / metabolism
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Humans
  • Imatinib Mesylate
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy
  • Phosphorylation
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrimidines / pharmacology*
  • Recombination, Genetic*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Alkylating
  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Chlorambucil
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-abl
  • DNA-Activated Protein Kinase
  • nilotinib