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Identification of effective retinoids for inhibiting growth and inducing apoptosis in bladder cancer cells
1Department of Obstetrics and Gynecology, University of Texas, Medical School, Houston, Texas, USA.
Purpose:
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.
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-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.
Results:
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.
Conclusions:
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.
Insights
4-(N-hydroxyphenyl) retinamide (4HPR) effectively inhibits bladder cancer cell growth and induces apoptosis, outperforming other retinoids. Resistance to all-trans-retinoic acid may stem from a lack of retinoic acid receptor beta expression.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Retinoids are known to modulate epithelial cell growth and differentiation, with potential in preventing and treating bladder cancer.
- Existing retinoid analogs have been evaluated in clinical trials for superficial bladder cancer recurrence.
- Novel retinoids and treatment strategies are needed for superficial bladder cancer chemoprevention and therapy.
Purpose of the Study:
- To investigate the efficacy of various retinoids in inhibiting bladder cancer cell growth.
- To assess the ability of retinoids to induce apoptosis in bladder cancer cell lines.
- To explore the relationship between retinoid treatment, receptor expression, and apoptosis-related gene modulation.
Main Methods:
- Utilized ten grades 1 to 3 bladder cancer cell lines.
- Tested four retinoids: all-trans-retinoic acid, 9-cis retinoic acid, 4-(N-hydroxyphenyl) retinamide (4HPR), and LGD1069.
- Compared retinoid effects on cell growth, apoptosis induction, nuclear retinoid receptor expression, and apoptosis-related gene expression.
Main Results:
- Most cell lines were resistant to all-trans-retinoic acid and 9-cis retinoic acid, often due to lack of retinoic acid receptor beta expression.
- 4-(N-hydroxyphenyl) retinamide (4HPR) demonstrated potent growth inhibition (approx. 90%) and induced apoptosis in most cell lines.
- LGD1069 showed minimal effect; 4HPR modulated bcl-2 expression but not p53, and its effects were independent of constitutive retinoic acid receptor beta expression.
Conclusions:
- 4-(N-hydroxyphenyl) retinamide (4HPR) is the most effective retinoid for inhibiting bladder cancer cell growth and inducing apoptosis among those tested.
- Lack of retinoic acid receptor beta expression appears to confer resistance to all-trans-retinoic acid but not necessarily to other retinoids like 4HPR.
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