Construction of Dual Stimuli-Responsive Platinum(IV) Hybrids with NQO1 Targeting Ability and Overcoming Cisplatin Resistance

Inorg Chem. 2019 Feb 4;58(3):2191-2200. doi: 10.1021/acs.inorgchem.8b03386. Epub 2019 Jan 18.

Abstract

Quinone oxidoreductase isozyme I (NQO1) is a cytoprotective two-electron-specific reductase that highly expresses in various cancer cells. Taking NQO1 as the target, we herein report three hybrid compounds from Pt(IV) complexes and a quinone propionic acid unit. The mechanism studies showed that the hybrids could be activated by both NQO1 and ascorbic acid to release the cytotoxic Pt(II) unit, exhibiting a dual stimuli-responsive character. In the pharmacological studies, complexes 2 and 3 presented higher antitumor activity than cisplatin. More importantly, the hybrid could also overcome cisplatin resistance due to the NQO1 targeting ability, improved cellular uptake, and/or different action mechanism. Significantly, complex 3 containing a coumarin moiety could be effectively activated in NQO1-overexpressed cancer cells to "turn on" fluorescence, showing a promising visual effect in cancer cells. In vivo study revealed that both 2 and 3 exhibited higher antitumor efficacy than cisplatin in the A549 xenograft mouse model at an equimolar dose to cisplatin. In all, the hybrids may serve as promising NQO1-targeting anticancer agents.

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cisplatin / chemistry
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Screening Assays, Antitumor
  • Hep G2 Cells
  • Humans
  • Mice
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors*
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Platinum / chemistry
  • Platinum / pharmacology*

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Platinum
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Cisplatin