Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts

PLoS One. 2014 Jan 13;9(1):e80836. doi: 10.1371/journal.pone.0080836. eCollection 2014.

Abstract

Purpose: Uveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines.

Experimental design: Four well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC).

Results: S44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration.

Conclusion: The novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Fluorescence Polarization
  • Heterocyclic Compounds, 3-Ring / administration & dosage
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Heterocyclic Compounds, 3-Ring / therapeutic use*
  • Humans
  • Immunohistochemistry
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mice, SCID
  • Molecular Targeted Therapy*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Nitrosourea Compounds / pharmacology
  • Nitrosourea Compounds / therapeutic use
  • Organophosphorus Compounds / pharmacology
  • Organophosphorus Compounds / therapeutic use
  • Peptides / metabolism
  • Protein Binding / drug effects
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use*
  • Survival Analysis
  • Uveal Neoplasms / drug therapy*
  • Uveal Neoplasms / metabolism
  • Uveal Neoplasms / pathology
  • Xenograft Model Antitumor Assays*
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Heterocyclic Compounds, 3-Ring
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrosourea Compounds
  • Organophosphorus Compounds
  • Peptides
  • S44563
  • Sulfonamides
  • bcl-X Protein
  • fotemustine

Supplementary concepts

  • Uveal melanoma

Grants and funding

The study was supported by Servier Laboratories. However, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.