Adamantanyl-histone deacetylase inhibitor H6CAHA exhibits favorable pharmacokinetics and augments prostate cancer radiation sensitivity
Abstract
Purpose To evaluate pharmacological properties of H6CAHA, an adamantyl-hydroxamate histone deacetylase inhibitor, and to investigate its effect on prostate cancer cells following exposure to γ-radiation in vitro and in vivo. Methods and materials H6CAHA was assessed for in vitro solubility, lipophilicity and growth inhibition, and in vivo plasma pharmacokinetics. The effect of H6CAHA on radiation clonogenic survival and DNA damage repair was evaluated in human prostate cancer (PC3, DU145, LNCaP) and nonmalignant control epithelial (RWPE1 and 267B1) cell lines. The effect of this agent on the growth of prostate cancer xenografts was also assessed in mice. Results H6CAHA demonstrated good solubility and permeability profiles and preferentially inhibited the growth of prostate cancer cells over nonmalignant cells. Plasma pharmacokinetics revealed that the area under the curve of H6CAHA was 8.08 ± 0.91 μM × h, and its half-life was 11.17 ± 0.87 h. Radiation clonogenic assays revealed that H6CAHA decreased the survival of prostate cancer cells at the dose that exerted limited effect on normal cells. Concomitantly, delayed DNA damage repair following combination treatment was evident in cancer cells, indicated by the prolonged appearance of γH2AX and Rad51 foci and suppression of DNA damage repair genes (ATM, BRCA1, and BRCA2). Combined modality of H6CAHA (daily intraperitoneal injections for 10 days) with γ-radiation (10 × 2 Gy) completely blocked the growth of PC3 tumor xenograft…
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The novel HDAC inhibitors W2 (mercaptoacetamide-based class II) and I2 (hydroxamide-based class I and II) have improved pharmacological properties, including longer half-life and greater blood-brain barrier penetration, compared to commercially available HDACIs.
“We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2)”
From Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease (2013) · cites this paper as Konsoula, et al., 2011
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Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer
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Sung, Y. M., Lee, T., Yoon, H., DiBattista, A. M., Song, J. M., Sohn, Y., Moffat, E. I., Turner, R. S., Jung, M., Kim, J., et al. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2012.10.005 · Cited by 137 · see citing works
Self-citationAdhikari, N., Jha, T., & Ghosh, B. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01676 · Cited by 74 · see citing works
- Authors
- Konsoula, Z., Cao, H., Velena, A., & Jung, M.
- Affiliations
- Georgetown University (US)
- Corresponding author
- Jung, Mira
- Venue
- International Journal of Radiation Oncology*Biology*Physics
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 79
- Issue
- 5
- Pages
- 1541-1548
- ISSN
- 0360-3016 (ISSN-L)
- OpenAlex
- W2007656363
- Cited by
- 27
- References
- 2
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2014: 5 · 2013: 7 · 2012: 2
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Radiation Oncology*Biology*Physics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- histone deacetylase inhibitors, prostate cancer, radiosensitization, pharmacokinetics, DNA repair, clonogenic survival, γH2AX, RAD51 foci, ATM, BRCA1, BRCA2, tumor xenografts, combination therapy
- MeSH terms
- Adamantane, Animals, Cell Line, Cell Survival, DNA Damage, DNA Repair, DNA-Binding Proteins, Gamma Rays, Half-Life, Histones, Humans, Hydroxamic Acids, Male, Mice, Nude, Prostatic Neoplasms, Radiation Tolerance, Radiation-Sensitizing Agents, Tumor Stem Cell Assay, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Genes, BRCA1, Area Under Curve, Xenograft Model Antitumor Assays, Genes, BRCA2, Tumor Suppressor Proteins, Cell Line, Tumor, Rad51 Recombinase, Mice, Histone Deacetylase Inhibitors, Ataxia Telangiectasia Mutated Proteins
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