Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death.
Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Delta-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU 210 all caused morphological changes characteristic of apoptosis. Janus green assays of H460 cell viability showed that AEA and THC caused significant increases in OD 595 nm at lower concentrations (10-50 microM) and significant decreases at 100 microM, whilst HU 210 caused significant decreases at all concentrations. In rat heart mitochondria, all three ligands caused significant decreases in oxygen consumption and mitochondrial membrane potential. THC and HU 210 caused significant increases in mitochondrial hydrogen peroxide production, whereas AEA was without significant effect. All three ligands induced biphasic changes in either mitochondrial complex I activity and/or mitochondrial complex II-III activity. These data demonstrate that AEA, THC, and HU 210 are all able to cause changes in integrated mitochondrial function, directly, in the absence of cannabinoid receptors.
Athanasiou
Andriani
A
School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Clarke
Anna B
AB
Turner
Amy E
AE
Kumaran
Nethia M
NM
Vakilpour
Sara
S
Smith
Paul A
PA
Bagiokou
Dimitra
D
Bradshaw
Tracey D
TD
Westwell
Andrew D
AD
Fang
Lin
L
Lobo
Dileep N
DN
Constantinescu
Cris S
CS
Calabrese
Vittorio
V
Loesch
Andrzej
A
Alexander
Stephen P H
SP
Clothier
Richard H
RH
Kendall
David A
DA
Bates
Timothy E
TE
D017209:Apoptosis / Q000187:drug effects*; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D042967:Electron Transport Complex I / Q000187:drug effects; D042963:Electron Transport Complex II / Q000187:drug effects; D014450:Electron Transport Complex III / Q000187:drug effects; D063388:Endocannabinoids; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008175:Lung Neoplasms; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D008954:Models, Biological; D010101:Oxygen Consumption / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D013759:Dronabinol; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; C062018:HU 211; C078814:anandamide