Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: how vanilloids cause non-vanilloid receptor mediated cell death.
Time-lapse photomicroscopy of human H460 lung cancer cells demonstrated of the transient receptor potential V1 (TRPV1) channel agonists, (E)-capsaicin and resiniferatoxin, and the TRPV1 antagonists, capsazepine, and SB366791, were able to bring about morphological changes characteristic of apoptosis and/or necrosis. Immunoblot analysis identified immunoreactivity for the transient receptor potential V1 (TRPV1) channel in rat brain samples, but not in rat heart mitochondria or in H460 cells. In isolated rat heart mitochondria, all four ligands caused concentration-dependent decreases in oxygen consumption and mitochondrial membrane potential. (E)-Capsaicin and capsazepine evoked concentration-dependent increases and decreases, respectively, in mitochondrial hydrogen peroxide production, whilst resiniferatoxin and SB366791 were without significant effect. These data support the hypothesis that (E)-capsaicin, resiniferatoxin, capsazepine, and SB366791 are all mitochondrial inhibitors, able to activate apoptosis and/or necrosis via non-receptor mediated mechanisms, and also support the use of TRPV1 ligands as anti-cancer agents.
Athanasiou
Andriani
A
School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Smith
Paul A
PA
Vakilpour
Sara
S
Kumaran
Nethia M
NM
Turner
Amy E
AE
Bagiokou
Dimitra
D
Layfield
Robert
R
Ray
David E
DE
Westwell
Andrew D
AD
Alexander
Stephen P H
SP
Kendall
David A
DA
Lobo
Dileep N
DN
Watson
Susan A
SA
Lophatanon
Artitaya
A
Muir
Kenneth A
KA
Guo
De-An
DA
Bates
Timothy E
TE
D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
D000813:Anilides; D002934:Cinnamates; D004224:Diterpenes; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C024353:resiniferatoxin; D006861:Hydrogen Peroxide; C071423:capsazepine; D002211:Capsaicin