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.