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Histone Deacetylase Inhibitors and Bladder Cancer
Histone Deacetylase Inhibitors and Bladder Cancer BLADDER cancer represents a serious health care burden worldwide. At any given time, more than 500,000 people in the United States have had or are currently living with a diagnosis of bladder cancer. Bladder cancer is also the most expensive solid tumor to treat, primarily as a result of its high recurrence rate and need for continued surveillance.1 With age and smoking the 2 most common risk factors, the incidence of bladder cancer and associated costs will only increase in the coming decades as people live longer and the impact of smoking manifests across the globe. As with other solid tumors, efforts are being made to develop rational therapeutic strategies based on the underlying biology of bladder cancer. One recent area of interest has been the role of epigenetic changes in regulating bladder tumor biology. Epigenetic modifications, such as methylation and acetylation of DNA and histones, have profound effects on chromatin conformation, accessibility of DNA to transcriptional regulators and gene expression. Histone acetyltransferases and histone deacetylases (HDACs) regulate the acetylation state of both histones and nonhistone proteins by catalyzing the addition or removal, respectively, of acetyl groups on lysine residues. Through neutralization of positive charge, acetylation decreases binding of histones to DNA, resulting in a more open chromatin conformation and enhancing transcription. Conversely, deacetylation by HDACs restores DNA-histone binding, thereby returning chromatin to a closed state and repressing transcription. HDACs are divided into 4 distinct classes based on function, subcellular location and relative sensitivity to inhibitors. HDAC inhibitors (HDACis) currently number more than 15 agents that can be grouped into several classes based on chemical structure.2 These include short chain fatty acids, benzamides, hydroxamic acid compounds and cyclic tetrapeptides, of which all inhibit histone deacetylation with potency in the nanomolar to micromolar range in vitro. The demonstration that HDACis could inhibit cell cycle transit and promote differentiation or apoptosis of transformed cells led to their investigation 0022-5347/10/1836-2120/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
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as potential anticancer agents. The mechanisms whereby HDACis achieve their antitumor activity effects have not been fully elucidated. However, multiple HDACis have been shown to induce expression of the cyclin dependent kinase inhibitors p21WAF1, p27Kip1 and p16INK4A, leading to cell cycle arrest.3 In this issue of The Journal Gould et al (page 2395) report on the use of reverse phase protein arrays to profile the modulation of tumor suppressor and invasion associated proteins in 9 bladder cancer cell lines exposed to a panel of HDACis. They noted differential up-regulation and down-regulation of several mediators of cell migration, including ␥ and ␣-catenin, gelsolin, desmoglein and focal adhesion kinase. Previous studies from this group have shown antitumor activity of the hydroxamic acid compound trichostatin A (TSA) on bladder cancer cells in vitro and against bladder cancer xenografts in vivo.4 Followup of these observations showed that re-expression of ␥-catenin (also known as junction plakoglobin), as occurs following HDACi administration, reduced tumor cell migration and attenuated tumorigenic potential in vivo,5 providing a mechanistic basis for the observed antitumor effects of HDACi. Similar inhibitory effects were observed with belinostat (PXD101) in the UPII-Ha-ras transgenic model of superficial bladder cancer, as evidenced by decreased bladder weight, hematuria, tumor size and mitotic index of bladder tumors.6 A number of investigators have reported the ability of multiple HDACis (valproic acid, TSA, sodium phenylbutyrate and FR901228) to increase expression of the Coxsackie and adenovirus receptor (CAR), the high affinity receptor for adenovirus type 5 and a key component of the transduction apparatus for adenovirus based gene therapy. Several reports have indicated decreased CAR expression in urological cancers, potentially limiting the efficacy of adenoviral vector transfer to target cells. Conversely, restoration of CAR expression by treatment with HDACi would be predicted to circumvent this limitation. El-Zawahry et al verified the functional significance of increased CAR expression secondary to TSA treatment by reporting enhanced infectivity Vol. 183, 2120-2121, June 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.03.047
HISTONE DEACETYLASE INHIBITORS AND BLADDER CANCER
of T24 bladder cancer cells with adenoviral-tumor necrosis factor-related apoptosis-inducing ligand and a corresponding increase in apoptosis.7 A number of HDACis have undergone preclinical and clinical testing with provocative results. Although somewhat limited in scope with respect to bladder cancer, there have been some promising outcomes. In phase I trials, intravenous or oral vorinostat (also known as suberoylanilide hydroxamic acid) showed modest activity against bladder cancer, eliciting either minor objective responses or stable disease, although improvements in tumor related pain were reported.8,9 Another trial tested the oral HDACi CI-994 in combination with carboplatin and paclitaxel, and included 2 patients with bladder cancer, of whom 1 showed a complete response.10 However, no correlation between the clinical response and changes in histone acetylation was observed. Thus, the tumor inhibitory effect of CI-994 independently of carboplatin and paclitaxel could not be assessed. In general, HDACis have been well tolerated in patients and show good bioavailability with effective in vivo concentrations achieved despite rapid elimi-
2121
nation. Moreover, limited toxicity has been reported when used in combination with conventional cytotoxic chemotherapy, with minimal dose titration of either HDACi or chemotherapeutic agents required. As with all drugs, lack of selectivity and off target effects remain a concern. For example, valproic acid, in addition to its HDAC inhibitory activity, also inhibits T-type calcium channels and voltage gated sodium channels, which may contribute to the cardiotoxicity reported in clinical trials.2 In addition, there is the potential for considerable redundancy with the HDAC enzyme family, such that targeting of 1 HDAC or class of HDACs may simply lead to compensatory activity of other family members and a loss of antitumor effects. However, in spite of these concerns, preliminary findings in patients suggest that creative combination of HDACis with other targeted and conventional chemotherapeutic agents is likely to enhance the therapeutic options for bladder cancer and other solid tumors in the coming decade. Rosalyn M. Adam Urological Diseases Research Center Children’s Hospital Boston Boston, Massachusetts
REFERENCES 1. Horner MJ, Ries LAG, Krapcho M et al: SEER Cancer Statistics Review, 1975–2006. Bethesda: National Cancer Institute 2008.
antineoplastic activity in vitro and in vivo. Int J Cancer 2005; 113: 841.
2. Lane AA and Chabner BA: Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 2009; 27: 5459.
5. Rieger-Christ KM, Ng L, Hanley RS et al: Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. Br J Cancer 2005; 92: 2153.
3. Carew JS, Giles FJ and Nawrocki ST: Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett 2008; 269: 7.
6. Buckley MT, Yoon J, Yee H et al: The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo. J Transl Med 2007; 5: 49.
4. Canes D, Chiang GJ, Billmeyer BR et al: Histone deacetylase inhibitors upregulate plakoglobin expression in bladder carcinoma cells and display
7. El-Zawahry A, Lu P, White SJ et al: In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of
CAR expression and downregulation of cFLIP and Bcl-XL. Cancer Gene Ther 2006; 13: 281. 8. Kelly WK, Richon VM, O’Connor O et al: Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003; 9: 3578. 9. Kelly WK, O’Connor OA, Krug LM et al: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005; 23: 3923. 10. Pauer LR, Olivares J, Cunningham C et al: Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors. Cancer Invest 2004; 22: 886.
2120
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AND
RESEARCH, INC.
as potential anticancer agents. The mechanisms whereby HDACis achieve their antitumor activity effects have not been fully elucidated. However, multiple HDACis have been shown to induce expression of the cyclin dependent kinase inhibitors p21WAF1, p27Kip1 and p16INK4A, leading to cell cycle arrest.3 In this issue of The Journal Gould et al (page 2395) report on the use of reverse phase protein arrays to profile the modulation of tumor suppressor and invasion associated proteins in 9 bladder cancer cell lines exposed to a panel of HDACis. They noted differential up-regulation and down-regulation of several mediators of cell migration, including ␥ and ␣-catenin, gelsolin, desmoglein and focal adhesion kinase. Previous studies from this group have shown antitumor activity of the hydroxamic acid compound trichostatin A (TSA) on bladder cancer cells in vitro and against bladder cancer xenografts in vivo.4 Followup of these observations showed that re-expression of ␥-catenin (also known as junction plakoglobin), as occurs following HDACi administration, reduced tumor cell migration and attenuated tumorigenic potential in vivo,5 providing a mechanistic basis for the observed antitumor effects of HDACi. Similar inhibitory effects were observed with belinostat (PXD101) in the UPII-Ha-ras transgenic model of superficial bladder cancer, as evidenced by decreased bladder weight, hematuria, tumor size and mitotic index of bladder tumors.6 A number of investigators have reported the ability of multiple HDACis (valproic acid, TSA, sodium phenylbutyrate and FR901228) to increase expression of the Coxsackie and adenovirus receptor (CAR), the high affinity receptor for adenovirus type 5 and a key component of the transduction apparatus for adenovirus based gene therapy. Several reports have indicated decreased CAR expression in urological cancers, potentially limiting the efficacy of adenoviral vector transfer to target cells. Conversely, restoration of CAR expression by treatment with HDACi would be predicted to circumvent this limitation. El-Zawahry et al verified the functional significance of increased CAR expression secondary to TSA treatment by reporting enhanced infectivity Vol. 183, 2120-2121, June 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.03.047
HISTONE DEACETYLASE INHIBITORS AND BLADDER CANCER
of T24 bladder cancer cells with adenoviral-tumor necrosis factor-related apoptosis-inducing ligand and a corresponding increase in apoptosis.7 A number of HDACis have undergone preclinical and clinical testing with provocative results. Although somewhat limited in scope with respect to bladder cancer, there have been some promising outcomes. In phase I trials, intravenous or oral vorinostat (also known as suberoylanilide hydroxamic acid) showed modest activity against bladder cancer, eliciting either minor objective responses or stable disease, although improvements in tumor related pain were reported.8,9 Another trial tested the oral HDACi CI-994 in combination with carboplatin and paclitaxel, and included 2 patients with bladder cancer, of whom 1 showed a complete response.10 However, no correlation between the clinical response and changes in histone acetylation was observed. Thus, the tumor inhibitory effect of CI-994 independently of carboplatin and paclitaxel could not be assessed. In general, HDACis have been well tolerated in patients and show good bioavailability with effective in vivo concentrations achieved despite rapid elimi-
2121
nation. Moreover, limited toxicity has been reported when used in combination with conventional cytotoxic chemotherapy, with minimal dose titration of either HDACi or chemotherapeutic agents required. As with all drugs, lack of selectivity and off target effects remain a concern. For example, valproic acid, in addition to its HDAC inhibitory activity, also inhibits T-type calcium channels and voltage gated sodium channels, which may contribute to the cardiotoxicity reported in clinical trials.2 In addition, there is the potential for considerable redundancy with the HDAC enzyme family, such that targeting of 1 HDAC or class of HDACs may simply lead to compensatory activity of other family members and a loss of antitumor effects. However, in spite of these concerns, preliminary findings in patients suggest that creative combination of HDACis with other targeted and conventional chemotherapeutic agents is likely to enhance the therapeutic options for bladder cancer and other solid tumors in the coming decade. Rosalyn M. Adam Urological Diseases Research Center Children’s Hospital Boston Boston, Massachusetts
REFERENCES 1. Horner MJ, Ries LAG, Krapcho M et al: SEER Cancer Statistics Review, 1975–2006. Bethesda: National Cancer Institute 2008.
antineoplastic activity in vitro and in vivo. Int J Cancer 2005; 113: 841.
2. Lane AA and Chabner BA: Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 2009; 27: 5459.
5. Rieger-Christ KM, Ng L, Hanley RS et al: Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. Br J Cancer 2005; 92: 2153.
3. Carew JS, Giles FJ and Nawrocki ST: Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett 2008; 269: 7.
6. Buckley MT, Yoon J, Yee H et al: The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo. J Transl Med 2007; 5: 49.
4. Canes D, Chiang GJ, Billmeyer BR et al: Histone deacetylase inhibitors upregulate plakoglobin expression in bladder carcinoma cells and display
7. El-Zawahry A, Lu P, White SJ et al: In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of
CAR expression and downregulation of cFLIP and Bcl-XL. Cancer Gene Ther 2006; 13: 281. 8. Kelly WK, Richon VM, O’Connor O et al: Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003; 9: 3578. 9. Kelly WK, O’Connor OA, Krug LM et al: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005; 23: 3923. 10. Pauer LR, Olivares J, Cunningham C et al: Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors. Cancer Invest 2004; 22: 886.