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

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 mitochondrial membrane potential, an increase in resting respiration, an inhibition of Ca(2+) influx, stimulation of Ca(2+) efflux in Ca(2+)-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.

• Authors: Felippe H Z Reis, Gilberto L Pardo-Andreu, Yanier Nuñez-Figueredo, Osmany Cuesta-Rubio, Javier Marín-Prida, Sérgio A Uyemura, Carlos Curti, Luciane C Alberici
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 212 Pg. 20-9 (Apr 05 2014) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 24491676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 7-epiclusianone
• Antineoplastic Agents
• Benzophenones
• Benzoquinones
• Biological Products
• Bridged Bicyclo Compounds
• Reactive Oxygen Species
• Uncoupling Agents
• nemorosone
• NAD
• Adenosine Triphosphate
• Calcium

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Benzophenones (chemistry, pharmacology)
• Benzoquinones
• Biological Products (chemistry, pharmacology)
• Biological Transport (drug effects)
• Bridged Bicyclo Compounds (chemistry, pharmacology)
• Calcium (metabolism)
• Cell Death (drug effects)
• Cell Respiration (drug effects)
• Hep G2 Cells
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria, Liver (drug effects, metabolism)
• NAD (metabolism)
• Osmotic Pressure (drug effects)
• Rats
• Reactive Oxygen Species (metabolism)
• Stereoisomerism
• Structure-Activity Relationship
• Uncoupling Agents (chemistry, pharmacology)