Innovative DNA-Targeted Metallo-prodrug Strategy Combining Histone Deacetylase Inhibition with Oxidative Stress

Mol Pharm. 2018 Nov 5;15(11):5058-5071. doi: 10.1021/acs.molpharmaceut.8b00652. Epub 2018 Oct 2.

Abstract

Cancer remains a global health challenge. There is an urgent need to develop innovative therapeutics that can overcome the shortcomings of existing cancer therapies. DNA enzymes involved in nucleic acid compaction and organization are an attractive cancer drug target for therapeutic exploitation. In this work, a family of Cu(II) prodrugs containing suberoylanilide hydroxamic acid (SAHA), a well-established histone deacetylase inhibitor (HDACi) and clinically approved cancer drug, and phenanthrene ligands as DNA intercalative components have been rationally developed. The complexes, of general formula [Cu(SAHA-1H)( N, N'-phenanthrene)]+, exhibit excellent DNA recognition with binding affinity of lead agents in the order of ∼107 M(bp)-1. Biophysical studies involving nucleic acid polymers indicate intercalative binding at both adenine-thymine (A-T) and guanine-cytosine (G-C) rich sequences but thermodynamically stable interactions are favored in G-C tracts. The complexes mediate DNA damage by producing reactive oxygen species (ROS) with spin trapping experiments showing that superoxide, the hydroxyl radical, and hydrogen peroxide play critical roles in strand scission. The agents were found to have promising antiproliferative effects against a panel of epithelial cancers, and in two representative cell lines possessing mutated p53 (SK-OV-3 and DU145), enhanced cytotoxicity was observed. Significantly, mechanistic experiments with the most promising candidates revealed HDAC inhibition activity was achieved over a shorter time frame as compared to clinical standards with DNA damage-response markers identifying upregulation of both DNA synthesis and nucleotide excision repair (NER) pathways. Finally, confocal imaging and gene expression analysis show this metallodrug class exerts cytotoxic activity predominantly through an apoptotic pathway.

Keywords: Cu(II); DNA; histone deacetylases (HDAC); metallodrug; nuclease agent; reactive oxygen species (ROS); suberoylanilide hydroxamic acid (SAHA).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Copper / chemistry
  • Copper / pharmacology
  • Copper / therapeutic use
  • DNA / chemistry
  • DNA Damage / drug effects
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Intercalating Agents / chemistry
  • Intercalating Agents / pharmacology*
  • Intercalating Agents / therapeutic use
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology*
  • Organometallic Compounds / therapeutic use
  • Oxidative Stress / drug effects
  • Phenanthrenes / chemistry
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Prodrugs / therapeutic use
  • Vorinostat / chemistry

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Intercalating Agents
  • Organometallic Compounds
  • Phenanthrenes
  • Prodrugs
  • Vorinostat
  • Copper
  • DNA