Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo

Clin Cancer Res. 2005 Jul 1;11(13):4851-6. doi: 10.1158/1078-0432.CCR-04-2160.

Abstract

We have previously identified the retinoid X receptor-alpha (RXRalpha) as an insulin-like growth factor binding protein-3 (IGFBP-3) nuclear binding partner, which is required for IGFBP-3-induced apoptosis. In the current study, we investigated the biological interactions of the RXR ligand, VTP194204 and rhIGFBP-3, in vitro and in vivo. In vitro, IGFBP-3 and VTP194204 individually induced apoptosis, and suppressed cell growth in prostate cancer cell lines in an additive manner. In vivo, LAPC-4 xenograft-bearing severe combined immunodeficiency mice treated daily with saline, IGFBP-3, and/or VTP194204 for 3 weeks showed no effect of individual treatments with IGFBP-3 or VTP194204 on tumor growth. However, the combination of IGFBP-3 and VTP194204 treatments inhibited tumor growth by 50% and induced a significant reduction in serum prostate-specific antigen levels. In terminal nucleotidyl transferase-mediated nick end labeling immunohistochemistry of LAPC-4 xenografts, there was modest induction of apoptosis with either IGFBP-3 or VTP194204 individual treatment, but combination therapy resulted in massive cell death, indicating that IGFBP-3 and VTP194204 have a synergistic effect in preventing tumor growth by apoptosis induction. In summary, this is an initial description of the successful therapeutic use of IGFBP-3 as a cancer therapy in vivo, and shows that combination treatment of IGFBP-3 and RXR ligand has a synergistic effect on apoptosis induction leading to substantial inhibition of prostate cancer xenograft growth. Taken together, these observations suggest that combination therapy with IGFBP-3 and RXR ligands may have therapeutic potential for prostate cancer treatment.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Drug Synergism
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / administration & dosage
  • Insulin-Like Growth Factor Binding Protein 3 / pharmacology*
  • Ligands
  • Male
  • Mice
  • Mice, SCID
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Retinoid X Receptors / metabolism
  • Retinoids / administration & dosage
  • Retinoids / metabolism
  • Retinoids / pharmacology*
  • Time Factors
  • Xenograft Model Antitumor Assays

Substances

  • Insulin-Like Growth Factor Binding Protein 3
  • Ligands
  • Retinoid X Receptors
  • Retinoids
  • Prostate-Specific Antigen