Clusianone, a naturally occurring nemorosone regioisomer, uncouples rat liver mitochondria and induces HepG2 cell death

Author(s)

Reis, Felippe H. Z. ^[1] ; Pardo-Andreu, Gilberto L. ^{[1, 2]} ; Nunez-Figueredo, Yanier ^[3] ; Cuesta-Rubio, Osmany ^[4] ; Marin-Prida, Javier ^[2] ; Uyemura, Sergio A. ^{[5, 6]} ; Curti, Carlos ^{[1, 5]} ; Alberici, Luciane C. ^{[1, 5]}

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Quim & Fis, Ribeirao Preto, SP - Brazil

^[2] Univ La Habana, Inst Farm & Alimentos, Ctr Estudio Invest & Evaluac Biol, Havana 13600 - Cuba

^[3] Ctr Invest & Desarrollo Medicamentos, Havana - Cuba

^[4] Univ La Habana, Inst Farm & Alimentos, Dept Farm, Havana 13600 - Cuba

^[5] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Nucleo Pesquisas Prod Nat & Sintet, Ribeirao Preto, SP - Brazil

^[6] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Chemico-Biological Interactions; v. 212, p. 20-29, APR 5 2014.
• Web of Science Citations: 8

Abstract

Clusianone is a member of the polycyclic polyprenylated acylphloroglucinol family of natural products; its cytotoxic mechanism is unknown. Clusianone is a structural isomer of nemorosone, which is a mitochondrial uncoupler and a well-known cytotoxic anti-cancer agent; thus, we addressed clusianone action at the mitochondria and its potential cytotoxic effects on cancer cells. In the HepG2 hepatocarcinoma cell line, clusianone induced mitochondrial membrane potential dissipation, ATP depletion and phosphatidyl serine externalization; this later event is indicative of apoptosis induction. In isolated mitochondria from rat liver, clusianone promoted protonophoric mitochondrial uncoupling. This was evidenced by the dissipation of mitochondria(membrane potential, an increase in resting respiration, an inhibition of Ca2+ influx, stimulation of Ca2+ efflux in Ca2+-loaded mitochondria, a decrease in ATP and NAD(P)H levels, generation of ROS, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. The cytotoxic and uncoupling actions of clusianone were appreciably less than those of nemorosone, likely due to the presence of an intra-molecular hydrogen bond with the juxtaposed carbonyl group at the C15 position. Therefore, clusianone is capable of pharmacologically increasing the leakage of protons from the mitochondria and with favorable cytotoxicity in relation to nemorosone. (C) 2014 Elsevier Ireland Ltd. All rights reserved. (AU)

• FAPESP's process: 10/17259-9 - Studies on mechanisms of mitochondrial uncoupling by non-esterified fatty acids as a strategy for prevention / treatment of obesity
• Grantee: Luciane Carla Alberici
• Support Opportunities: Research Grants - Young Investigators Grants