Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells

Exp Hematol. 2006 Dec;34(12):1663-9. doi: 10.1016/j.exphem.2006.07.008.

Abstract

Objective: Antiapoptotic Bcl-2 is overexpressed in most cases of chronic lymphocytic leukemia (CLL). The inhibition of the antiapoptotic Bcl-2 proteins is an attractive strategy for either restoring normal apoptotic process in cancer cells or making these cells more susceptible to conventional chemotherapy. We studied the effect of Bcl-2 inhibitors on the viability of cells from CLL and other mature B-cell neoplasms.

Materials and methods: We studied the cytotoxic effects of four nonpeptidic cell-permeable Bcl-2 inhibitors (HA14-1, antimycin A, GX15-003, and GX15-070) on B cells from patients with CLL, mantle cell lymphoma (MCL), and splenic marginal zone lymphoma (SMZL). Moreover, we analyzed the effect of these inhibitors in combination with fludarabine or chlorambucil.

Results: HA14-1 induced apoptosis with an EC50 lower than 50 microM in 26 of the 36 CLL samples analyzed. The mean EC50 for these sensitive patients was 23 +/- 2 microM. Antimycin A induced apoptosis in 13 of the 18 CLL samples analyzed. Both HA14-1 and antimycin A induced cytochrome c release from mitochondria and caspase-3 activation. Moreover, HA14-1 induced apoptosis in peripheral cells from MCL and SMZL. HA14-1 also induced apoptosis in CLL samples with alterations in p53 or ATM. Finally, GX compounds induced apoptosis in B cells from 9 of the 11 CLL samples tested. The combination of either HA14-1, antimycin A, or GX compounds with fludarabine or chlorambucil had additive cytotoxic effects on CLL cells.

Conclusion: Bcl-2 inhibitors induce apoptosis in CLL cells ex vivo and could be used in CLL as monotherapy or given in combination with current chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimycin A / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects*
  • Benzopyrans / pharmacology*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Lymphoma, Mantle-Cell / drug therapy
  • Lymphoma, Mantle-Cell / metabolism*
  • Nitriles / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Pyrroles / pharmacology*
  • Splenic Neoplasms / drug therapy
  • Splenic Neoplasms / metabolism*

Substances

  • Benzopyrans
  • Nitriles
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
  • Antimycin A
  • obatoclax