The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications

Toxicol Appl Pharmacol. 2011 Jun 15;253(3):282-9. doi: 10.1016/j.taap.2011.04.011. Epub 2011 Apr 27.


Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 μM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca²⁺ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analysis
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Benzophenones / pharmacokinetics
  • Benzophenones / pharmacology*
  • Calcium / metabolism
  • Cell Survival / drug effects
  • Energy Metabolism / drug effects
  • Hep G2 Cells
  • Humans
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Mitochondrial Membranes / drug effects*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Swelling / drug effects
  • NAD / analysis
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism


  • Antineoplastic Agents, Phytogenic
  • Benzophenones
  • Reactive Oxygen Species
  • guttiferone A
  • NAD
  • Adenosine Triphosphate
  • Calcium