title: 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.
authors.affiliation: Centro de Estudio para las Investigaciones y Evaluaciones Biológicas, Instituto de Farmacia y Alimentos, Universidad de La Habana, Ave. 23 # 21425 e/214 and 222, La Coronela, La Lisa, CP 13600, Ciudad Habana, Cuba. gilbertopardo@infomed.sld.cu
authors.forename: Gilberto L
authors.initials: GL
authors.lastname: Pardo-Andreu
authors.forename: Yanier
authors.initials: Y
authors.lastname: Nuñez-Figueredo
authors.forename: Valeria G
authors.initials: VG
authors.lastname: Tudella
authors.forename: Osmany
authors.initials: O
authors.lastname: Cuesta-Rubio
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Rodrigues
authors.forename: Cezar R
authors.initials: CR
authors.lastname: Pestana
authors.forename: Sérgio A
authors.initials: SA
authors.lastname: Uyemura
authors.forename: Andreia M
authors.initials: AM
authors.lastname: Leopoldino
authors.forename: Luciane C
authors.initials: LC
authors.lastname: Alberici
authors.forename: Carlos
authors.initials: C
authors.lastname: Curti
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001577:Benzophenones / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009243:NAD / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001577:Benzophenones; D017382:Reactive Oxygen Species; C558133:guttiferone A; D009243:NAD; D000255:Adenosine Triphosphate; D002118:Calcium