Induction of Apoptosis by N-(4-Hydroxyphenyl)retinamide and Its Association with Reactive Oxygen Species, Nuclear Retinoic Acid Receptors, and Apoptosis-Related Genes in Human Prostate Carcinoma Cells

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Vol. 55, Issue 3, 403-410, March 1999

Induction of Apoptosis by N-(4-Hydroxyphenyl)retinamide and Its Association with Reactive Oxygen Species, Nuclear Retinoic Acid Receptors, and Apoptosis-Related Genes in Human Prostate Carcinoma Cells

Shi-Yong Sun, Ping Yue, and Reuben Lotan

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) has been shown to induce apoptosis in various malignant cellsincluding human prostate carcinoma cells (HPC). We examined severalpossible mechanisms by which 4HPR could induce apoptosis in HPCcells. 4HPR exhibited concentration- and time-dependent decreasein cell number both in androgen-dependent (LNCaP) and -independent(DU145 and PC-3) cells. The 4HPR concentrations causing 50% decreasein cell number in LNCaP, DU145, and PC-3 cultures were 0.9 ± 0.16,4.4 ± 0.45, and 3.0 ± 1.0 µM, respectively, indicating that LNCaPcells were more sensitive to 4HPR than the other cells. 4HPR-inducedapoptosis in all three cell lines was evidenced by increased enzymaticlabeling of DNA breaks and formation of a DNA ladder. 4HPR increasedthe level of reactive oxygen species, especially in LNCaP cells.4HPR-induced apoptosis could be suppressed in LNCaP cells by antioxidantand in DU145 cells by a nuclear retinoic acid receptor-specificantagonist, suggesting the involvement of reactive oxygen speciesor retinoic acid receptors in mediating apoptosis induced by 4HPRin the different HPC cells. Furthermore, 4HPR modulated the expressionlevels of some apoptosis-related gene (p21, c-myc, and c-jun),which may also contribute to the induction of apoptosis by 4HPRin HPCcells.

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				H.-J. Kim and R. Lotan Identification of Retinoid-Modulated Proteins in Squamous Carcinoma Cells Using High-Throughput Immunoblotting Cancer Res., April 1, 2004; 64(7): 2439 - 2448. [Abstract] [Full Text] [PDF]

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				S.-Y. Sun, P. Yue, G. J. Kelloff, V. E. Steele, S. M. Lippman, W. K. Hong, and R. Lotan Identification of Retinamides That Are More Potent than N-(4-Hydroxyphenyl)retinamide in Inhibiting Growth and Inducing Apoptosis of Human Head and Neck and Lung Cancer Cells Cancer Epidemiol. Biomarkers Prev., June 1, 2001; 10(6): 595 - 601. [Abstract] [Full Text] [PDF]

				M.-J. Don, Y.-H. Chang, K.-K. Chen, L.-K. Ho, and Y.-P. Chau Induction of CDK Inhibitors (p21WAF1 and p27Kip1) and Bak in the {beta}-Lapachone-Induced Apoptosis of Human Prostate Cancer Cells Mol. Pharmacol., April 1, 2001; 59(4): 784 - 794. [Abstract] [Full Text]

				A. Senchenkov, D. A. Litvak, and M. C. Cabot Targeting Ceramide Metabolism--a Strategy for Overcoming Drug Resistance J Natl Cancer Inst, March 7, 2001; 93(5): 347 - 357. [Abstract] [Full Text] [PDF]

				C. Thaller, M. Shalev, A. Frolov, G. Eichele, T. C. Thompson, R. H. Williams, O. Dillioglugil, and D. Kadmon Fenretinide Therapy in Prostate Cancer: Effects on Tissue and Serum Retinoid Concentration J. Clin. Oncol., November 15, 2000; 18(22): 3804 - 3808. [Abstract] [Full Text] [PDF]