title: Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.
abstract: Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.
authors: The Dr. Miriam and Sheldon G Adelson Center for the Biology of Addictive Diseases, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: N
authors: N
authors: Rimmerman
authors: D
authors: D
authors: Ben-Hail
authors: Z
authors: Z
authors: Porat
authors: A
authors: A
authors: Juknat
authors: E
authors: E
authors: Kozela
authors: M P
authors: MP
authors: Daniels
authors: P S
authors: PS
authors: Connelly
authors: E
authors: E
authors: Leishman
authors: H B
authors: HB
authors: Bradshaw
authors: V
authors: V
authors: Shoshan-Barmatz
authors: Z
authors: Z
authors: Vogel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002185:Cannabidiol / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D005434:Flow Cytometry; D051379:Mice; D017628:Microglia / Q000187:drug effects; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002186:Cannabinoids; C494762:VDAC1 protein, human; D002185:Cannabidiol; D050995:Voltage-Dependent Anion Channel 1