Dataset Information

Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors.

ABSTRACT: 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 nonsteroidal 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 noncancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type-selective responses.

SUBMITTER: Gryder BE

PROVIDER: S-EPMC3836611 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors.

Gryder Berkley E BE Akbashev Michelle J MJ Rood Michael K MK Raftery Eric D ED Meyers Warren M WM Dillard Paulette P Khan Shafiq S Oyelere Adegboyega K AK

ACS chemical biology 20130920 11

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 effectiv ...[more]

PMID: 24004176

Similar Datasets

Project description:BackgroundIonizing radiation (IR) is a standard modality for the management of solid tumors. Apart from its killing effects, IR can induce pro-survival factors leading to radioresistance of cancer. Mechanistic understanding of radiation resistance is warranted to overcome the pro-survival effects of IR.AimThe aim of this study was to investigate the role of upstream stimulatory factor-1 (USF-1) in the induction of radioresistance in prostate cancer and its targeting by histone deacetylase (HDAC) inhibitors to reverse resistance.Methods and resultsThis study reports here that USF-1 is a marker for radioresistance in PC-3 cells. Using protein-DNA array analysis, it was documented that DNA binding activity of USF-1 was elevated following IR in PC-3 cells. Novel HDAC inhibitors downregulated USF-1 binding either alone or in combination with IR. A 5 Gy dose of IR induced the expression of target genes of USF-1 (human telomerase reverse transcriptase [hTERT], IGF2R, CyclinB1, and Cdk1), however, HDAC inhibitors alone or in combination with IR reduced their expression as measured by real time RT PCR analysis. Furthermore, immunofluorescence analysis revealed that while USF-1 localized primarily in the nucleus following IR, it localized in the cytoplasm when treated with HDAC inhibitors/combination. Maximum effects of modulation of USF-1 expression (overexpression or suppression) were observed on hTERT activity as determined by dual-luciferase reporter assay. To further confirm the role of USF-1 in radioresistance, cell growth was analyzed using the real-time cell electronic sensing (RT-CES) system. This study found that USF-1-transfected cells proliferated faster than the vector-transfected cells with or without treatments with HDAC inhibitors/IR/combination. Colony forming assay also confirmed that USF-1 overexpression led to increased survival following IR. Importantly, colony-forming assay demonstrated that HDAC inhibitors reversed the radioresistance in both PC-3 and DU-145 cells.ConclusionThese studies demonstrate that HDAC inhibitors reverse the radioresistance in prostate cancer through down-modulation of USF-1-mediated transactivation of target genes involved in cell proliferation and cell cycle.

Dataset Information

Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors.

Publications

Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets