Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy Ashutosh Shrivastava, Paula M. Kuzontkoski, Jerome E. Groopman, et al.
Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD mediates this activity is yet to be elucidated. Here, we have shown CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation. Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis. Western blot analysis confirmed these findings. We showed that CBD induces endoplasmic reticulum stress and, subsequently, inhibits AKT and mTOR signaling as shown by decreased levels of phosphorylated mTOR and 4EBP1, and cyclin D1. Analyzing further the cross-talk between the autophagic and apoptotic signaling pathways, we found that beclin1 plays a central role in the induction of CBD-mediated apoptosis in MDA-MB-231 breast cancer cells. Although CBD enhances the interaction between beclin1 and Vps34, it inhibits the association between beclin1 and Bcl-2. In addition, we showed that CBD reduces mitochondrial membrane potential, triggers the translocation of BID to the mitochondria, the release of cytochrome c to the cytosol, and, ultimately, the activation of the intrinsic apoptotic pathway in breast cancer cells. CBD increased the generation of reactive oxygen species (ROS), and ROS inhibition blocked the induction of apoptosis and autophagy. Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent.
Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling* Estefanía Moreno 1,2,3,† , Clara Andradas 4,5,† , Mireia Medrano 1,2,3,† , María M. Caffarel 4,6 Eduardo Pérez-Gómez 4,5 , Sandra Blasco-Benito 4,5, María Gómez-Cañas 7,2,8 , M Ruth Pazos 7,2 , Andrew J.Irving 9 , Carme Lluís 1,2,3 , Enric I. Canela 1,2,3 , Javier Fernández-Ruiz 7,2,8 , Manuel Guzmán 2,4,8 , Peter J. McCormick 1,2,3,10* , Cristina Sánchez 4,5*
1 Dept. Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain 2 Centro de Investigación Biomédica en Red de Enfe rmedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain 3 Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain 4 Dept. Biochemistry and Molecular Biology I, School of Biology / Instituto Universitario de Investigación en Neuroquímica, School of Medicine, Complutense University, 28040 Madrid, Spain 5 Instituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain 6 Present address: Dept. Pathology, University of Cambridge, CB2 1QP Cambridge, UK 7 Dept. Biochemistry and Molecular Biology III / Instituto Universitario de Investigación en Neuroquímica, School of Medicine, Complutense University, 28040 Madrid, Spain 8 Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) 9 Division of Neuroscience, Ninewells Hospital, University of Dundee, DD1 9SY Dundee, UK 10 School of Pharmacy, University of East Anglia, Norwich Research Park, NR4 7TJ Norwich, UK
Abstract The G protein-coupled receptors CB2(CB2R) and GPR55 are overexpressed in cancer cells and human tumors. As a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here, we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo . These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.
Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival Jahan P. Marcu1, Rigel T. Christian1, Darryl Lau1, Anne J. Zielinski1, Maxx P. Horowitz1, Jasmine Lee1, Arash Pakdel1, Juanita Allison1,Chandani Limbad1, Dan H. Moore1,2, Garret L. Yount1, Pierre-Yves Desprez1 and Sean D. McAllister1
Abstract The cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonist Δ9-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB1 and CB2 receptors, can modulate the actions of Δ9-THC. There are conflicting reports, however, as to what extent other cannabinoids can modulate Δ9-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Δ9-THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Δ9-THC. In the U251 and SF126 glioblastoma cell lines, Δ9-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Δ9-THC may improve the overall effectiveness of Δ9-THC in the treatment of glioblastoma in cancer patients.
Delta-9-tetrahydrocannabinol may palliate
altered chemosensory perception in cancer patients: results of a
placebo-controlled pilot trial T. D. Brisbois1, H. de Kock2, S. M. Watanabe2,M. Mirhosseini2,D. C. Lamoureux2, M. Chasen3, N. MacDonald4, V. E. Baracos2 and W. V. Wismer1,*
Background: A pilot study (NCT00316563) to determine if delta-9-tetrahydrocannabinol (THC) can improve taste and smell (chemosensory) perception as well as appetite,
caloric intake, and quality of life (QOL) for cancer patients with chemosensory alterations.
Patients and methods: Adult advanced cancer patients, with poor appetite and chemosensory alterations, were recruited from two sites and randomized
in a double-blinded manner to receive either THC (2.5 mg, Marinol®; Solvay Pharma Inc., n = 24) or placebo oral capsules (n
= 22) twice daily for 18 days. Twenty-one patients completed the trial.
At baseline and posttreatment, patients completed
a panel of patient-reported outcomes: Taste and
Smell Survey, 3-day food record, appetite and macronutrient preference
QOL questionnaire, and an interview.
Results: THC and placebo groups were comparable at baseline. Compared with placebo, THC-treated patients reported improved (P = 0.026) and enhanced (P < 0.001) chemosensory perception and food ‘tasted better’ (P = 0.04). Premeal appetite (P = 0.05) and proportion of calories consumed as protein increased compared with placebo (P = 0.008). THC-treated patients reported increased quality of sleep (P = 0.025) and relaxation (P = 0.045). QOL scores and total caloric intake were improved in both THC and placebo groups.
Conclusions: THC may be useful in the palliation of chemosensory alterations and to improve food enjoyment for cancer patients.