Identification of effective retinoids for inhibiting growth and inducing apoptosis in bladder cancer cells

Purpose: Retinoids modulate the growth and differentiation of normal and ma lignant epithelial cells in vitro and in vivo, and inhibit bladder carcinog enesis in animal models. Retinoid analogs have been used in several clinica l chemoprevention trials of superficial bladder cancer recurrence. There is a clear need to identify new effective retinoids and develop novel approac hes for the chemoprevention and treatment of superficial bladder cancer. We investigated the effects of various retinoids on growth inhibition and apo ptosis induction in bladder cancer cell lines. Materials and Methods: Ten grades 1 to 3 bladder cancer cell lines and the 4 retinoids all-trans-retinoic acid, 9-cis retinoic acid, 4-(N-hydroxypheny l) retinamide (4HPR) and LGD1069 were used in the study. We compared the ab ility of these retinoids to inhibit growth, induce apoptosis, affect the ex pression of nuclear retinoid receptors and modulate apoptosis related genes . Results: Most bladder cancer cell lines did not express retinoic acid recep tor 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 c oncentration of 10(-5) M. The 2 cell lines that expressed retinoic acid rec eptor beta were constitutively sensitive to the growth inhibitory effect of all-trans-retinoic acid. 4HPR inhibited cell growth by about 90% in all bu t I 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 cance r 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. Conclusions: The results demonstrate that 4HPR is the most potent growth in hibitor and apoptosis inducer of the retinoids tested. Lack of retinoic aci d receptor beta expression may be responsible for cell resistance to all-tr ans-retinoic acid but not to the other retinoids.