Cannabinoids and Cancer
- Cell Physiol Biochem. 2016 Nov 2;39(6):2149-2157. [Epub ahead of print]
WIN 55,212-2 Inhibits the Epithelial Mesenchymal Transition of Gastric Cancer Cells via COX-2 Signals.
Xian X(1), Huang L, Zhang B, Wu C, Cui J, Wang Z.
(1)Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
BACKGROUND: Cannabinoids (the active components of Cannabis sativa) and their derivatives have received considerable interest due to reports that they can affect the tumor growth, migration, and metastasis. Previous studies showed that the cannabinoid agonist WIN 55,212-2 (WIN) was associated with gastric cancer(GC) metastasis, but the mechanisms were unknown.
METHODS: The effects of WIN on GC cell migration and invasion were analyzed by
the wound-healing assay and Transwell assay. Quantitative real-time PCR and Western blot were used to evaluate changes in expression of COX-2 and EMT associated markers in SGC7901 and AGS cells.
RESULTS: WIN inhibited cell migration, invasion, and epithelial to mesenchymal transition (EMT) in GC. WIN treatment resulted in the downregulation of cyclooxygenase-2 (COX-2) expression and decreased the phosphorylation of AKT, and inhibited EMT in SGC7901 cells. Decreased expression of COX-2 and vimentin, and increased expression of E-cadherin, which was induced by WIN, were normalized by overexpression of AKT, suggesting that AKT mediated, at least partially, the WIN suppressed EMT of GC cells. CONCLUSION: WIN can inhibit the EMT of GC cells through the downregulation of COX-2.
© 2016 The Author(s) Published by S. Karger AG, Basel.
- Autophagy. 2016 Nov;12(11):2213-2229. Epub 2016 Sep 16.
Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization.
Hernández-Tiedra S(1,)(2), Fabriàs G(3), Dávila D(1,)(2), Salanueva ÍJ(1), Casas J(3), Montes LR(4), Antón Z(4), García-Taboada E(1), Salazar-Roa M(1), Lorente M(1,)(2), Nylandsted J(5), Armstrong J(6,)(7), López-Valero I(1,)(2), McKee CS(6), Serrano-Puebla A(1,)(8), García-López R(1), González-Martínez J(1,)(2), Abad JL(3), Hanada K(9), Boya P(8), Goñi F(4), Guzmán M(1,)(10), Lovat P(6), Jäättelä M(5), Alonso A(4), Velasco G(1,)(2).
(1)a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain. (2)b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain. (3)c Research Unit on BioActive
Molecules (RUBAM) , Departments of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona , Spain. (4)d Biofisika Institute (UPV/EHU, CSIC) , and Departamento de Bioquímica, Universidad del País Vasco, Barrio Sarriena s/n , Leioa , Spain. (5)e Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center (DCRC) , Copenhagen , Denmark. (6)f Dermatological Sciences , Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne , UK. (7)g Faculty of Applied Sciences, University of Sunderland , Sunderland , UK. (8)h Departament
of Cellular and Molecular Biology , Centro de Investigaciones Biológicas, CSIC , Madrid , Spain. (9)i Department of Biochemistry and Cell Biology , National Institute of Infectious Diseases , Shinjuku-ku, Tokyo , Japan.
(10)j Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto
Ramón y Cajal de Investigación Sanitaria, Madrid, Spain, Instituto Universitario
de Investigación Neuroquímica, Complutense University , Madrid , Spain.
Autophagy is considered primarily a cell survival process, although it can also lead to cell death. However, the factors that dictate the shift between these 2 opposite outcomes remain largely unknown. In this work, we used Δ(9)-tetrahydrocannabinol (THC, the main active component of marijuana, a compound that triggers autophagy-mediated cancer cell death) and nutrient deprivation (an autophagic stimulus that triggers cytoprotective autophagy) to investigate the precise molecular mechanisms responsible for the activation of cytotoxic autophagy in cancer cells. By using a wide array of experimental approaches we show that THC (but not nutrient deprivation) increases the dihydroceramide:ceramide ratio in the endoplasmic reticulum of glioma cells, and this alteration is directed to autophagosomes and autolysosomes to promote lysosomal membrane permeabilization, cathepsin release and the subsequent activation of apoptotic cell death. These findings pave the way to clarify the
regulatory mechanisms that determine the selective activation of
autophagy-mediated cancer cell death.
- Adv Exp Med Biol. 2016;952:31-34.
Damaging Effects of Cannabis Use on the Lungs.
Yayan J(1), Rasche K(2).
Cannabis is the most widely smoked illicit substance in the world. It can be smoked alone in its plant form, marijuana, but it can also be mixed with tobacco.
The specific effects of smoking cannabis are difficult to assess accurately and to distinguish from the effects of tobacco; however its use may produce severe consequences. Cannabis smoke affects the lungs similarly to tobacco smoke,causing symptoms such as increased cough, sputum, and hyperinflation. It can also cause serious lung diseases with increasing years of use. Cannabis can weaken the
immune system, leading to pneumonia. Smoking cannabis has been further linked with symptoms of chronic bronchitis. Heavy use of cannabis on its own can cause airway obstruction. Based on immuno-histopathological and epidemiological evidence, smoking cannabis poses a potential risk for developing lung cancer. At present, however, the association between smoking cannabis and the development of lung cancer is not decisive.
- Int J Mol Med. 2016 Oct 17. doi: 10.3892/ijmm.2016.2779. [Epub ahead of print]
Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review).
Dobovišek L(1), Hojnik M(1), Ferk P(1).
(1)Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia.
The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments. On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target. The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately.
Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2. Most of these influence cell proliferative activity. Better insight into this association may prove to be
beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis. The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted.
- Int J Cancer.
Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.
Barbado MV(1), Medrano M(1), Caballero-Velázquez T(1), Álvarez-Laderas I(1),Sánchez-Abarca LI(1), García-Guerrero E(1), Martín-Sánchez J(1), Rosado IV(1),Piruat JI(1), Gonzalez-Naranjo P(2), Campillo NE(2), Páez JA(2), Pérez-Simón JA(3).
(1)Institute of Biomedicine of Sevilla (IBIS/CSIC), Department of Hematology,University Hospital Virgen del Rocío, Universidad de Sevilla, Spain. (2)Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain. (3)Institute of Biomedicine of Sevilla (IBIS/CSIC), Department of Hematology, University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined. Here we have investigated their anti-tumor effect in multiple myeloma (MM). We demonstrate that cannabinoids induce a selective
apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells.
This effect was mediated by caspase activation, mainly caspase-2, and was
partially prevented by a pan-caspase inhibitor. Their pro-apoptotic effect was correlated with an increased expression of Bax and Bak, a decrease of Bcl-xL and
Mcl-1, a biphasic response of Akt/PKB and an increase in the levels of ceramide in MM cells. Inhibition of ceramide synthesis partially prevented apoptosis, indicating that these sphingolipids play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis. Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to
melphalan in vitro. Finally, administration of cannabinoid WIN-55 to
plasmacytoma-bearing mice significantly suppressed tumor growth in vivo.
Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM.
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