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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

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          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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          Most cited references35

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          Protein-binding assays in biological liquids using microscale thermophoresis.

          Protein interactions inside the human body are expected to differ from the situation in vitro. This is crucial when investigating protein functions or developing new drugs. In this study, we present a sample-efficient, free-solution method, termed microscale thermophoresis, that is capable of analysing interactions of proteins or small molecules in biological liquids such as blood serum or cell lysate. The technique is based on the thermophoresis of molecules, which provides information about molecule size, charge and hydration shell. We validated the method using immunologically relevant systems including human interferon gamma and the interaction of calmodulin with calcium. The affinity of the small-molecule inhibitor quercetin to its kinase PKA was determined in buffer and human serum, revealing a 400-fold reduced affinity in serum. This information about the influence of the biological matrix may allow to make more reliable conclusions on protein functionality, and may facilitate more efficient drug development.
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            Role of the mitochondrial membrane permeability transition in cell death.

            In recent years, the role of the mitochondria in both apoptotic and necrotic cell death has received considerable attention. An increase of mitochondrial membrane permeability is one of the key events in apoptotic or necrotic death, although the details of the mechanism involved remain to be elucidated. The mitochondrial membrane permeability transition (MPT) is a Ca(2+)-dependent increase of mitochondrial membrane permeability that leads to loss of Deltapsi, mitochondrial swelling, and rupture of the outer mitochondrial membrane. The MPT is thought to occur after the opening of a channel that is known as the permeability transition pore (PTP), which putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT), cyclophilin D (Cyp D: a mitochondrial peptidyl prolyl-cis, trans-isomerase), and other molecule(s). Recently, significant progress has been made by studies performed with mice lacking Cyp D at several laboratories, which have convincingly demonstrated that Cyp D is essential for the MPT to occur and that the Cyp D-dependent MPT regulates some forms of necrotic, but not apoptotic, cell death. Cyp D-deficient mice have also been used to show that the Cyp D-dependent MPT plays a crucial role in ischemia/reperfusion injury. The anti-apoptotic proteins Bcl-2 and Bcl-x(L) have the ability to block the MPT, and can therefore block MPT-dependent necrosis in addition to their well-established ability to inhibit apoptosis.
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              Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

              Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9)-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9)-tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                December 2013
                05 December 2013
                1 December 2013
                : 4
                : 12
                : e949
                Affiliations
                [1 ]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
                [2 ]The Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev , Beer-Sheva, Israel
                [3 ]The Flow Cytometry Unit, Weizmann Institute of Science , Rehovot, Israel
                [4 ]National Heart Lung and Blood Institute , Bethesda, MD, USA
                [5 ]The Department of Psychological and Brain Sciences, Indiana University , Bloomington, IN, USA
                Author notes
                [* ]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 6997801, Israel. Tel: +972 3 6405615 or +972 8 9342995; Fax: +972 9 8345106; E-mail: Neta.rimmerman@ 123456weizmann.ac.il or Netarimm@ 123456post.tau.ac.il
                Article
                cddis2013471
                10.1038/cddis.2013.471
                3877544
                24309936
                0db84e05-846e-443c-9d3f-c9d9902be323
                Copyright © 2013 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 11 July 2013
                : 27 October 2013
                : 31 October 2013
                Categories
                Original Article

                Cell biology
                cannabidiol,cell death,cancer,microglia,mitochondria,voltage-dependent anion channel 1.
                Cell biology
                cannabidiol, cell death, cancer, microglia, mitochondria, voltage-dependent anion channel 1.

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