Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: A novel mechanism for cannabinoid-induced cell death

N. Rimmerman; D. Ben-Hail; Z. Porat; A. Juknat; E. Kozela; M. P. Daniels; P. S. Connelly; E. Leishman; H. B. Bradshaw; V. Shoshan-Barmatz; Z. Vogel

doi:10.1038/cddis.2013.471

Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: A novel mechanism for cannabinoid-induced cell death

N. Rimmerman^*, D. Ben-Hail, Z. Porat, A. Juknat, E. Kozela, M. P. Daniels, P. S. Connelly, E. Leishman, H. B. Bradshaw, V. Shoshan-Barmatz, Z. Vogel

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

132 Scopus citations

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.

Original language	English
Article number	e949
Journal	Cell Death and Disease
Volume	4
Issue number	12
DOIs	https://doi.org/10.1038/cddis.2013.471
State	Published - Dec 2013
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgements. This work was supported by the Dr. Miriam and Sheldon G Adelson Medical Research Foundation. AJ is supported by the Israeli Ministry for Absorption in Science. We thank Dr. Or Golan and Professor Asher Shainberg from The Cancer Research Center, Bar Ilan University, Ramat Gan, Israel, for the preliminary experiments on mitochondrial membrane potential.

Keywords

cancer
cannabidiol
cell death
microglia
mitochondria
voltage-dependent anion channel 1

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10.1038/cddis.2013.471

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Rimmerman, N., Ben-Hail, D., Porat, Z., Juknat, A., Kozela, E., Daniels, M. P., Connelly, P. S., Leishman, E., Bradshaw, H. B., Shoshan-Barmatz, V., & Vogel, Z. (2013). Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: A novel mechanism for cannabinoid-induced cell death. Cell Death and Disease, 4(12), Article e949. https://doi.org/10.1038/cddis.2013.471

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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.",

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note = "Funding Information: Acknowledgements. This work was supported by the Dr. Miriam and Sheldon G Adelson Medical Research Foundation. AJ is supported by the Israeli Ministry for Absorption in Science. We thank Dr. Or Golan and Professor Asher Shainberg from The Cancer Research Center, Bar Ilan University, Ramat Gan, Israel, for the preliminary experiments on mitochondrial membrane potential.",

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Rimmerman, N, Ben-Hail, D, Porat, Z, Juknat, A, Kozela, E, Daniels, MP, Connelly, PS, Leishman, E, Bradshaw, HB, Shoshan-Barmatz, V & Vogel, Z 2013, 'Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: A novel mechanism for cannabinoid-induced cell death', Cell Death and Disease, vol. 4, no. 12, e949. https://doi.org/10.1038/cddis.2013.471

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AU - Ben-Hail, D.

AU - Porat, Z.

AU - Juknat, A.

AU - Kozela, E.

AU - Daniels, M. P.

AU - Connelly, P. S.

AU - Leishman, E.

AU - Bradshaw, H. B.

AU - Shoshan-Barmatz, V.

AU - Vogel, Z.

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N2 - 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.

AB - 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.

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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

Bibliographical note

Keywords

UN SDGs

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