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An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Hana Kostrhunova1, Emanuele Petruzzella2, Dan Gibson2

  • 1Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, CZ-61265, Brno, Czech Republic.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|February 12, 2019
PubMed

Insights

This study introduces a novel platinum(IV) prodrug that delivers cisplatin and epigenetic agents to cancer cells. This triple-action drug shows high potency against cisplatin-resistant tumors, offering a new cancer therapy approach.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Platinum(IV) prodrugs offer multi-action anticancer mechanisms via axial ligands.
  • Developing novel platinum-based chemotherapy with improved efficacy and reduced resistance is crucial.

Purpose of the Study:

  • To synthesize and evaluate a "triple-action" platinum(IV) prodrug.
  • To investigate its selective and potent anticancer activity, including against cisplatin-resistant cell lines.
  • To elucidate its multi-modal mechanism of action involving DNA modification and epigenetic regulation.

Main Methods:

  • Synthesis of a novel platinum(IV) prodrug.
  • In vitro evaluation of cytotoxicity using 2D monolayer and 3D spheroid cancer cell cultures.
  • Assessment of DNA covalent modification, histone deacetylase inhibition, and DNA methylation.
  • Pharmacological and molecular/cellular biology techniques.

Main Results:

  • The platinum(IV) prodrug demonstrated high potency (IC50 values as low as 9 nM) against various cancer cell lines, including cisplatin-resistant ones.
  • Cellular activation released platinum, inhibited histone deacetylase activity (via phenylbutyrate), and induced global DNA hypermethylation (via octanoate).
  • The prodrug exhibited over 100-fold greater activity than cisplatin in both 2D and 3D cell cultures.

Conclusions:

  • The developed platinum(IV) prodrug acts as a true multi-action agent, combining cytotoxic and epigenetic effects.
  • This novel prodrug represents a promising next-generation platinum anticancer drug with enhanced efficacy and a unique mechanism of action.
Keywords:
3D spheroidsDNA damageanticancer agentsepigenetic effectsplatinum prodrugs

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