Adamantanyl-histone deacetylase inhibitor H6CAHA exhibits favorable pharmacokinetics and augments prostate cancer radiation sensitivity

Int J Radiat Oncol Biol Phys. 2011 Apr 1;79(5):1541-8. doi: 10.1016/j.ijrobp.2010.11.057. Epub 2011 Jan 27.

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 xenografts (p < 0.001) over 60 days.

Conclusion: These results support the potential therapeutic value of H6CAHA in combination with radiation and support the rationale for further clinical investigation.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacokinetics
  • Adamantane / pharmacology
  • Animals
  • Area Under Curve
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • DNA Damage / drug effects
  • DNA Damage / physiology
  • DNA Repair / drug effects*
  • DNA-Binding Proteins / genetics
  • Gamma Rays / therapeutic use*
  • Genes, BRCA1
  • Genes, BRCA2
  • Half-Life
  • Histone Deacetylase Inhibitors / blood
  • Histone Deacetylase Inhibitors / pharmacokinetics*
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / pharmacology*
  • Male
  • Mice
  • Mice, Nude
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / radiotherapy*
  • Protein-Serine-Threonine Kinases / genetics
  • Rad51 Recombinase / metabolism
  • Radiation Tolerance / drug effects*
  • Radiation Tolerance / physiology
  • Radiation-Sensitizing Agents / pharmacokinetics
  • Radiation-Sensitizing Agents / pharmacology*
  • Tumor Stem Cell Assay / methods
  • Tumor Suppressor Proteins / genetics
  • Xenograft Model Antitumor Assays / methods

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • H2AX protein, human
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • N-hydroxy-6-(((adamantan-1-ylamino)carbonyl)amino)hexamide
  • Radiation-Sensitizing Agents
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • Rad51 Recombinase
  • Adamantane