Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice
| Autor: | C K Huynh, Vincent C. O. Njar, Angela Brodie |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Transplantation Heterologous Retinoic acid Apoptosis Tretinoin Mice SCID Biology azolyl retinoids Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine inhibitors LNCaP In Situ Nick-End Labeling medicine Animals Humans Liarozole Enzyme Inhibitors Cell Proliferation 030304 developmental biology all-trans-retinoic acid (ATRA) 0303 health sciences RAMBAs Cell growth catabolism Cell Cycle Prostatic Neoplasms Cell Differentiation 3. Good health CYP26 Endocrinology Gene Expression Regulation Oncology chemistry 030220 oncology & carcinogenesis Cancer cell Cancer research Growth inhibition Translational Therapeutics medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6602971 |
| Popis: | In recent studies, we have identified several highly potent all-trans-retinoic acid (ATRA) metabolism blocking agents (RAMBAs). On the basis of previous effects of liarozole (a first-generation RAMBA) on the catabolism of ATRA and on growth of rat Dunning R3227G prostate tumours, we assessed the effects of our novel RAMBAs on human prostate tumour (PCA) cell lines. We examined three different PCA cell lines to determine their capacity to induce P450-mediated oxidation of ATRA. Among the three different cell lines, enhanced catabolism was detected in LNCaP, whereas it was not found in PC-3 and DU-145. This catabolism was strongly inhibited by our RAMBAs, the most potent being VN/14-1, VN/50-1, VN/66-1, and VN/69-1 with IC50 values of 6.5, 90.0, 62.5, and 90.0 nM, respectively. The RAMBAs inhibited the growth of LNCaP cells with IC50 values in the microM-range. In LNCaP cell proliferation assays, VN/14-1, VN/50-1, VN/66-1, and VN/69-1 also enhanced by 47-, 60-, 70-, and 65-fold, respectively, the ATRA-mediated antiproliferative activity. We then examined the molecular mechanism underlying the growth inhibitory properties of ATRA alone and in combination with RAMBAs. The mechanism appeared to involve the induction of differentiation, cell-cycle arrest, and induction of apoptosis (TUNEL), involving increase in Bad expression and decrease in Bcl-2 expression. Treatment of LNCaP tumours growing in SCID mice with VN/66-1 and VN/69-1 resulted in modest but statistically significant tumour growth inhibition of 44 and 47%, respectively, while treatment with VN/14-1 was unexpectedly ineffective. These results suggest that some of our novel RAMBAs may be useful agents for the treatment of prostate cancer. |
| Databáze: | OpenAIRE |
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