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

We have previously identified the retinoid X receptor-α (RXRα) 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 rhI...

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Published in:	Clinical cancer research Vol. 11; no. 13; pp. 4851 - 4856
Main Authors:	BINGRONG LIU, LEE, Kuk-Wha, HEJU LI, LIQUN MA, LIN, George L, CHANDRARATNA, Roshantha A. S, COHEN, Pinchas
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-07-2005
Subjects:	Animals Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - therapeutic use apoptosis Apoptosis - drug effects Biological and medical sciences Cell Line, Tumor Drug Synergism Gynecology. Andrology. Obstetrics Humans Insulin-Like Growth Factor Binding Protein 3 - administration & dosage Insulin-Like Growth Factor Binding Protein 3 - pharmacology Insulin-like growth factor binding protein-3 Ligands Male Male genital diseases Medical sciences Mice Mice, SCID Nephrology. Urinary tract diseases Pharmacology. Drug treatments prostate cancer 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 RXR ligand Time Factors Tumors Tumors of the urinary system Urinary tract. Prostate gland Xenograft Model Antitumor Assays Urinary system disease Prostate disease Ligand Retinoid Malignant tumor In vitro In vivo Insulin-like growth factor binding protein-3 Cell death Combined treatment Male genital diseases Prostate cancer Tumor cell Apoptosis Biological receptor
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Summary:	We have previously identified the retinoid X receptor-α (RXRα) 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-04-2160