Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model

Mol Cancer. 2008 Feb 14;7:20. doi: 10.1186/1476-4598-7-20.

Abstract

Elevated expression of anti-apoptotic Bcl-2 family proteins have been linked to a poor survival rate of patients with Follicular Lymphoma (FL). This prompted us to evaluate a very potent non-peptidic Small-Molecule Inhibitor (SMI) targeting Bcl-2 family proteins, Apogossypolone (ApoG2) using follicular small cleaved cell lymphoma cell line (WSU-FSCCL) and cell isolated from lymphoma patients. ApoG2 inhibited the growth of WSU-FSCCL significantly with a 50% growth inhibition of cells (IC50) of 109 nM and decreased cell number of fresh lymphoma cells. ApoG2 activated caspases-9, -3, and -8, and the cleavage of Poly (ADP-ribose) polymerase (PARP) and Apoptosis Inducing Factor (AIF). In the WSU-FSCCL-SCID xenograft model, ApoG2 showed a significant anti-lymphoma effect, with %ILS of 84% in the intravenous and 63% in intraperitoneal treated mice. These studies suggest that ApoG2 can be an effective therapeutic agent against FL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis Regulatory Proteins / metabolism
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Female
  • Gossypol / chemistry
  • Gossypol / pharmacology
  • Gossypol / therapeutic use*
  • Humans
  • Inhibitory Concentration 50
  • Lymphocytes / drug effects
  • Lymphoma, Follicular / drug therapy*
  • Lymphoma, Follicular / enzymology
  • Mice
  • Mice, SCID
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / antagonists & inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Survival Analysis
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Poly(ADP-ribose) Polymerases
  • Caspases
  • Gossypol