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Innovative DNA-Targeted Metallo-prodrug Strategy Combining Histone Deacetylase Inhibition with Oxidative Stress
Tadhg J P McGivern1,2, Creina Slator2, Andrew Kellett2
1Centre for Synthesis and Chemical Biology, Department of Chemistry , Royal College of Surgeons in Ireland , 123 St. Stephen's Green , Dublin 2 , Ireland.
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.
Insights
New copper(II) prodrugs combining DNA intercalation and histone deacetylase inhibition show potent anticancer activity by inducing DNA damage and apoptosis, offering a promising therapeutic strategy against epithelial cancers.
Area of Science:
- Metallodrugs
- Cancer Therapeutics
- DNA Damage Mechanisms
Background:
- Cancer poses a significant global health challenge, necessitating novel therapeutic strategies beyond existing treatments.
- DNA enzymes and histone deacetylase inhibitors (HDACi) represent promising targets for cancer drug development.
- Suberoylanilide hydroxamic acid (SAHA) is a clinically approved HDACi with established anticancer effects.
Purpose of the Study:
- To rationally design and develop novel Cu(II) prodrugs incorporating SAHA and DNA-intercalating phenanthrene ligands.
- To investigate the DNA binding, DNA damaging capabilities, and antiproliferative effects of these metallodrugs.
- To elucidate the mechanism of action, including HDAC inhibition, DNA repair pathway modulation, and cell death induction.
Main Methods:
- Synthesis and characterization of Cu(II) complexes with SAHA and phenanthrene ligands.
- Biophysical studies (e.g., DNA binding affinity, sequence preference) using nucleic acid polymers.
- Assessment of reactive oxygen species (ROS) generation and DNA strand scission via spin trapping experiments.
- Evaluation of antiproliferative activity against various cancer cell lines, including those with mutated p53.
- Mechanistic studies involving HDAC inhibition assays, DNA damage-response marker analysis, confocal imaging, and gene expression analysis.
Main Results:
- The synthesized Cu(II) complexes exhibit strong DNA binding affinity (∼10^7 M(bp)^-1), favoring G-C rich sequences.
- These metallodrugs induce DNA damage through ROS production, leading to strand scission.
- Promising antiproliferative effects were observed against epithelial cancers, with enhanced cytotoxicity in p53-mutated cell lines.
- The agents demonstrated rapid HDAC inhibition and modulated DNA synthesis and nucleotide excision repair (NER) pathways.
- Cytotoxic activity was predominantly mediated through apoptosis.
Conclusions:
- The developed Cu(II)-SAHA-phenanthrene complexes represent a novel class of metallodrugs with significant anticancer potential.
- These agents effectively target cancer cells by inducing DNA damage, inhibiting HDACs, and triggering apoptosis.
- The findings support the therapeutic exploitation of DNA enzymes and HDAC inhibition for improved cancer treatment strategies.
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