Disruption of mitochondrial function as mechanism for anti-cancer activity of a novel mitochondriotropic menadione derivative

Toxicology. 2018 Jan 15;393:123-139. doi: 10.1016/j.tox.2017.11.014. Epub 2017 Nov 12.

Abstract

Menadione, also known as vitamin K3, is a 2-methyl-1,4 naphthoquinone with a potent cytotoxic activity mainly resulting from its quinone redox-cycling with production of reactive oxygen species (ROS). Although increased ROS generation is considered a relevant mechanism in cancer cell death, it may not be sufficiently effective to kill cancer cells due to phenotypic adaptations. Therefore, combining ROS-generating agents with other molecules targeting important cancer cell phenotypes can be an effective therapeutic strategy. As mitochondrial dysfunction has been implicated in many human diseases, including cancer, we describe here the discovery of a mitochondrial-directed agent (MitoK3), which was developed by conjugating a TPP cation to the C3 position of the menadione's naphthoquinone ring, increasing its selective accumulation in mitochondria, as well as led to alterations of its redox properties and consequent biological outcome. MitoK3 disturbed the mitochondrial bioenergetic apparatus, with subsequent loss of mitochondrial ATP production. The combinatory strategy of MitoK3 with anticancer agent doxorubicin (DOX) resulted in a degree of cytotoxicity higher than those of the individual molecules, as the combination triggered tumour apoptotic cell death evident by caspase 3/9 activities, probably through mitochondrial destabilization or by interference with mitochondrial redox processes. The results of this investigation support the importance of drug discovery process in developing molecules that can be use as adjuvant therapy in patients with specific cancer subtypes.

Keywords: Doxorubicin; Drug discovery; Menadione; Mitochondria; Mitochondriotropic menadione derivative.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenosine Triphosphate / metabolism
  • Adjuvants, Pharmaceutic / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Line
  • Cell Respiration / drug effects
  • Doxorubicin / pharmacology*
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxidation-Reduction
  • Oxygen Consumption
  • Rats
  • Vitamin K 3 / analogs & derivatives*
  • Vitamin K 3 / pharmacology*

Substances

  • Adjuvants, Pharmaceutic
  • Antineoplastic Agents
  • Vitamin K 3
  • Doxorubicin
  • Adenosine Triphosphate
  • Caspase 3
  • Caspase 9