Rodriguez-Enriquez 2019 Toxicol Appl Pharmacol
|Rodríguez-Enríquez S, Pacheco-Velázquez SC, Marín-Hernández Á, Gallardo-Pérez JC, Robledo-Cadena DX, Hernández-Reséndiz I, García-García JD, Belmont-Díaz J, López-Marure R, Hernández-Esquivel L, Sánchez-Thomas R, Moreno-Sánchez R (2019) Resveratrol inhibits cancer cell proliferation by impairing oxidative phosphorylation and inducing oxidative stress. Toxicol Appl Pharmacol 370:65-77.|
Rodriguez-Enriquez S, Pacheco-Velazquez SC, Marin-Hernandez A, Gallardo-Perez JC, Robledo-Cadena DX, Hernandez-Resendiz I, Garcia-Garcia JD, Belmont-Diaz J, Lopez-Marure R, Hernandez-Esquivel L, Sanchez-Thomas R, Moreno-Sanchez R (2019) Toxicol Appl Pharmacol
Abstract: The resveratrol (RSV) efficacy to affect the proliferation of several cancer cell lines was initially examined. RSV showed higher potency to decrease growth of metastatic HeLa and MDA-MB-231 (IC50 = 200-250 μM) cells than of low metastatic MCF-7, SiHa and A549 (IC50 = 400-500 μM) and non-cancer HUVEC and 3 T3 (IC50≥600 μM) cells after 48 h exposure. In order to elucidate the biochemical mechanisms underlying RSV anti-cancer effects, the energy metabolic pathways and the oxidative stress metabolism were analyzed in HeLa cells as metastatic-type cell model. RSV (200 μM/48 h) significantly decreased both glycolysis and oxidative phosphorylation (OxPhos) protein contents (30-90%) and fluxes (40-70%) vs. non-treated cells. RSV (100 μM/1-5 min) also decreased at a greater extent OxPhos flux (net ADP-stimulated respiration) of isolated tumor mitochondria (> 50%) than of non-tumor mitochondria (< 50%), particularly with succinate as oxidizable substrate. In addition, RSV promoted an excessive cellular ROS (2-3 times) production corresponding with a significant decrement in the SOD activity (but not in its content) and GSH levels; whereas the catalase, glutahione reductase, glutathione peroxidase and glutathione-S-transferase activities (but not their contents) remained unchanged. RSV (200 μM/48 h) also induced cellular death although not by apoptosis but rather by promoting a strong mitophagy activation (65%). In conclusion, RSV impaired OxPhos by inducing mitophagy and ROS over-production, which in turn halted metastatic HeLa cancer cell growth.
Copyright © 2019. Published by Elsevier Inc.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cancer Stress:Oxidative stress;RONS Organism: Rat Tissue;cell: Heart, Liver Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS Pathway: N, S HRR: Oxygraph-2k