Selectively Targeting Prostate Cancer with Antiandrogen Equipped Histone Deacetylase Inhibitors
| Autor: | Berkley E. Gryder, Michael K. Rood, Eric D. Raftery, Shafiq A. Khan, Paulette Dillard, Adegboyega K. Oyelere, Warren M. Meyers, Michelle J. Akbashev |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Biology Pharmacology Crystallography X-Ray Models Biological Biochemistry Article Chromatin remodeling Inhibitory Concentration 50 Drug Delivery Systems Cell Line Tumor Humans Cell Proliferation Histone deacetylase 5 Microscopy Confocal HDAC11 Histone deacetylase 2 HDAC10 Prostatic Neoplasms Androgen Antagonists General Medicine Histone acetyltransferase Histone Deacetylase Inhibitors Histone Receptors Androgen Cancer research biology.protein Molecular Medicine Histone deacetylase |
| Zdroj: | ACS Chemical Biology. 8:2550-2560 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/cb400542w |
| Popis: | Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with non-steroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone dependent (AR+) LNCaP and to a lesser extent against hormone independent (AR−) DU145 prostate cancer, while having greatly reduced toxicity in non-cancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type selective responses. |
| Databáze: | OpenAIRE |
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