Abstract
Coxsackie and adenovirus receptor (CAR) is known as a principal receptor for adenovirus commonly used as a gene delivery vector. Down-regulation of CAR is often detected in several cancer types. Epigenetic modifiers such as histone deacetylase inhibitor FK228 (depsipeptide) have been shown to increase CAR expression as well as the uptake of adenovirus in bladder cancer in vivo and in vitro, indicating that altered transcriptional regulation of CAR is the key mechanism responsible for the decreased CAR levels in this cancer. In this study, we screened agents that could induce CAR expression in bladder cancer cells. Fifty-eight drugs with various chemical properties were tested. Ipriflavone and plant isoflavones were found to exhibit the ability to induce CAR gene expression in combination with FK228. Genistein, the natural isoflavone found in soybean, when combined with FK228, exerts a synergistic effect on CAR gene and protein expression in bladder cancer cells. Chromatin immunoprecipitation results showed an increased histone acetylation in the CAR promoter gene, which is due to the suppression of histone deacetylase activity by both agents. Also, our data indicated that combination treatment is a potent chemotherapeutic regimen for bladder cancer cells and the subsequent administration of recombinant adenovirus could further eliminate the remaining cells. Taken together, our results provide a strong rationale for combining chemotherapeutic and gene therapeutic agents to enhance the therapeutic efficacy in bladder cancer.
Highlights
Transitional cell carcinoma (TCC) of the bladder is the second most common urological malignancy, and invasive disease has a poor prognosis
The decreased coxsackie and adenovirus receptor (CAR) expression in TCC certainly poses an obstacle for adenovirus-based gene therapy
We have found that the histone deacetylase (HDAC) inhibitor, FK228, is able to induce CAR gene expression in vitro [10] and in vivo [11]
Summary
Transitional cell carcinoma (TCC) of the bladder is the second most common urological malignancy, and invasive disease has a poor prognosis. Using genetic and molecular biology techniques, researchers have delineated many critical genes involved in TCC development. Many studies have shown that the exogenous delivery of these genes into TCC can alter the malignant phenotype of the tumor and/or eradicate it [1, 2]. Many studies have shown that coxsackie and adenovirus receptor (CAR), a high-affinity receptor for adenovirus type 5, is down-regulated in several cancer types [3, 4]. Several studies, including ours, have reported decreased CAR expression in TCC cell lines and tissue specimens [5,6,7,8,9]
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