Combination of N-(4-hydroxyphenyl) retinamide and genistein increased apoptosis in neuroblastoma SK-N-BE2 and SH-SY5Y xenografts.

Abstract

Neuroblastoma is the childhood malignancy that mainly occurs in adrenal glands and is found also in the neck, chest, abdomen, and pelvis. New therapeutic strategies are urgently needed for successful treatment of this pediatric cancer. In this investigation, we examined efficacy of the retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) and the isoflavonoid genistein (GST) alone and also in combination for controlling the growth of human malignant neuroblastoma SK-N-BE2 and SH-SY5Y xenografts in nude mice. Combination of 4-HPR and GST significantly reduced tumor volume in vivo due to overwhelming apoptosis in both neuroblastoma xenografts. Time-dependently, combination of 4-HPR and GST caused reduction in body weight, tumor weight, and tumor volume. Combination of 4-HPR and GST increased Bax:Bcl-2 ratio, mitochondrial release of Smac, downregulation of baculovirus inhibitor-of-apoptosis repeat containing (BIRC) proteins including BIRC-2 and BIRC-3, and activation of caspase-3 and apoptosis inducing factor (AIF). Further, downregulation of nuclear factor-kappa B (NF-kappaB), vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF2) was also detected. In situ immunofluorescent labelings of tumor sections showed overexpression of calpain, caspase-12, and caspase-3, and also AIF in the course of apoptosis. Combination therapy increased apoptosis in the xenografts but did not induce kidney and liver toxicities in the animals. Results demonstrated that combination of 4-HPR and GST induced multiple molecular mechanisms for apoptosis and thus could be highly effective for inhibiting growth of malignant neuroblastoma in preclinical animal models.

• Authors: S Karmakar, S Roy Choudhury, N L Banik, S K Ray
• Journal: Neuroscience (Neuroscience) Vol. 163 Issue 1 Pg. 286-95 (Sep 29 2009) ISSN: 1873-7544 [Electronic] United States
• PMID: 19540315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anticarcinogenic Agents
• Apoptosis Regulatory Proteins
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• Tretinoin
• retinamide
• Genistein

Topics

• Animals
• Anticarcinogenic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (drug effects, metabolism)
• Body Weight (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Genistein (therapeutic use)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Mice
• Mice, Nude
• NF-kappa B (drug effects, metabolism)
• Neuroblastoma (drug therapy, metabolism, physiopathology)
• Transplantation, Heterologous
• Treatment Outcome
• Tretinoin (analogs & derivatives, therapeutic use)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays