Identification of effective retinoids for inhibiting growth and inducing apoptosis in bladder cancer cells.
ABSTRACT Retinoids modulate the growth and differentiation of normal and malignant epithelial cells in vitro and in vivo, and inhibit bladder carcinogenesis in animal models. Retinoid analogs have been used in several clinical chemoprevention trials of superficial bladder cancer recurrence. There is a clear need to identify new effective retinoids and develop novel approaches for the chemoprevention and treatment of superficial bladder cancer. We investigated the effects of various retinoids on growth inhibition and apoptosis induction in bladder cancer cell lines.
Ten grades 1 to 3 bladder cancer cell lines and the 4 retinoids all-trans-retinoic acid, 9-cis retinoic acid, 4-(N-hydroxyphenyl) retinamide (4HPR) and LGD1069 were used in the study. We compared the ability of these retinoids to inhibit growth, induce apoptosis, affect the expression of nuclear retinoid receptors and modulate apoptosis related genes.
Most bladder cancer cell lines did not express retinoic acid receptor beta and were resistant to the effect of all-trans-retinoic acid and 9-cis retinoic acid on growth inhibition and apoptosis induction, even at a concentration of 10(-5) M. The 2 cell lines that expressed retinoic acid receptor beta were constitutively sensitive to the growth inhibitory effect of all-trans-retinoic acid. 4HPR inhibited cell growth by about 90% in all but 1 cell line and induced apoptosis at a concentration of 10(-5) M after a 24-hour treatment. LGD1069 had virtually no effect. All-trans-retinoic acid and 4HPR induced retinoic acid receptor beta expression in 1 bladder cancer cell line. However, the effect of 4HPR on cell growth and apoptosis were not related to the constitutive expression of retinoic acid receptor beta. 4HPR decreased bcl-2 expression in 6 of 8 bladder cancer cell lines but did not change p53 gene expression.
The results demonstrate that 4HPR is the most potent growth inhibitor and apoptosis inducer of the retinoids tested. Lack of retinoic acid receptor beta expression may be responsible for cell resistance to all-trans-retinoic acid but not to the other retinoids.
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ABSTRACT: Classical studies showed that retinoids were involved in many developmental processes. Retinoid acid receptors belong to one of the most complex subfamilies of the nuclear hormone receptor superfamily as both RAR and RXR receptors are encoded by a number of related genes each of which generates distinct isoforms. These isoforms are highly conserved between species and show complex stage and tissue specific patterns of expression, thus suggesting a molecular basis for the multiple effects of retinoids. However, the analysis of receptor knockout mutations generated in mice via homologous recombination, indicates a considerable underlying redundancy in receptor function.Seminars in Cell Biology 05/1994; 5(2):115-25.
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ABSTRACT: The nuclear receptors are a large family of ligand sensitive transcriptional regulators. They bind specific DNA sequences (response elements) in the promoter region of responsive genes. While the steroid hormone receptors bind as homodimers just two basic response elements, the retinoid and thyroid hormone receptor family interacts with a diverse set of response elements as homo- and heterodimers. The retinoid X receptors have a central role, since they form heterodimers with a whole subclass of receptors, consistent with the pleiotropic effects of retinoids. Differences in the mechanism of actions between steroid hormone receptors and other members of the family are discussed.Seminars in Cell Biology 05/1994; 5(2):95-103.
- Journal of Cellular Biochemistry - J CELL BIOCHEM. 01/1992; 50:139-147.