Title:Mitochondria-targeted Resveratrol Derivatives Act as Cytotoxic Pro-oxidants
Volume: 20
Issue: 2
Author(s): Nicola Sassi, Andrea Mattarei, Michele Azzolini, Paolo Bernardi, Ildiko' Szabo', Cristina Paradisi, Mario Zoratti and Lucia Biasutto
Affiliation:
Keywords:
Resveratrol, mitochondria, mitocans, cancer, reactive oxygen species.
Abstract: Resveratrol derivatives bearing an O-linked mitochondria-targeting 4-triphenylphosphoniumbutyl group at either position 3 or
position 4’ are prooxidant and cytotoxic for cultured cells, selectively killing fast-growing cells when supplied in the low μM range. Resveratrol
is essentially without effect under these experimental conditions, while the cytotoxicity of the mitochondriotropic derivatives increases
if they are methylated on the remaining hydroxyls. Experiments with Bax-/-/Bak-/- cells and a pan-caspase inhibitor show that cell
death is mostly of the necrotic type. Cytotoxicity is due to ROS produced upon accumulation of the compounds into mitochondria, and
specifically to H2O2, since externally added membrane-permeant catalase largely prevents cell death while superoxide dismutase potentiates
toxicity. The mitochondriotropic compounds cause ROS-independent depolarization of in situ mitochondria. Effectiveness is increased
if resveratrol hydroxyls are acetylated or methylated; this excludes the involvement of autooxidation of the polyphenolic nucleus
and a protonophoric cycle as the causes of ROS generation and of depolarization, respectively. Resveratrol-triphenylphosphonium conjugates
may thus represent a new class of chemotherapeutic agents, redox-active “mitocans”, whose mechanisms of action and in vivo activity
are worthy of further investigation.
