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

Abstract

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.

Pro-Oxidant Natural Products as Anticancer Agents

“…Two possible mechanisms may explain why the activation of glycolysis plays an important function in protecting tumor cells from H 2 O 2 -induced cell death. First, the activation of glycolysis increases the formation of pyru- Gentiacaulein Xanthone Gentiana kochiana (Gentianaceae) [187] Gentiakochianin Xanthone Gentiana kochiana (Gentianaceae) [187] Guttiferone-A Benzophenone Garcinia livingstonei (Clusiaceae) [188] Hesperetin Flavanone Citrus spp. (Rutaceae) [189,190] Hydroxytyrosol Simple Phenol Olea europaea (Oleaceae) [191] Icariin Flavonol glycoside Epimedium spp.…”

The cytotoxic effects of brown Cuban propolis depend on the nemorosone content and may be mediated by mitochondrial uncoupling

“…Brown Cuban propolis is the major group of Cuban propolis [5,7,10], and nemorosone is its main component [10,12]. We recently reported that nemorosone and its chemical analogues guttiferone A and clusianone presented strong cytotoxic effects mediated by mitochondrial uncoupling [13][14][15]. Therefore, it can be hypothesize that the http cytotoxic and antiparasitic effects of the brown Cuban propolis reported elsewhere [16,17] may be related to their nemorosone's content and mediated by a mitotoxic uncoupling effect.…”

Determination of macro, micro, trace essential, and toxic elements in Garcinia cambogia fruit and its anti‐obesity commercial products

“…Traditionally, its various species, distributed in Malaysia, India, Myanmar, Philippines, Sri Lanka, and Thailand, are used as flavoring and seasoning agents in curries and to cure several human health complications . Garcinia species are rich sources of bioactive xanthones, benzophenones, and flavonoidal constituents showing significant antioxidant, anti‐inflammatory, anticancer, anti‐HIV, hepatoprotective, and anticholinesterase activities …”