cannabinoids and cancer / Junio 2016

1. Recent Pat CNS Drug Discov. 2016 Jun 27.

Endocannabionoid System in Neurological Disorders.

Bifulco M, Laezza C, Malfitano AM(1).

Author information:
(1)Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, Baronissi, 84081 Salerno, Italy.

BACKGROUND: Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.

METHODS: In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.

RESULTS: Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis. Current treatments ameliorate the symptoms but are not curative. Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration. To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.

PMID: 27364363

2. Oncotarget. 2016 Jun 21. doi: 10.18632/oncotarget.10206.

Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer.

Andradas C(1,)(2), Blasco-Benito S(1,)(2), Castillo-Lluva S(1), Dillenburg-Pilla P(3), Diez-Alarcia R(4), Juanes-García A(5), García-Taboada E(1), Hernando-Llorente R(1), Soriano J(6), Hamann S(7), Wenners A(7), Alkatout I(7), Klapper W(8), Rocken C(8), Bauer M(7), Arnold N(7), Quintanilla M(9), Megías D(6), Vicente-Manzanares M(5), Urigüen L(4), Gutkind JS(3,)(10), Guzmán M(1,)(11), Pérez-Gómez E(1,)(2), Sánchez C(1,)(2).

Author information:
(1)Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain. (2)Instituto de Investigación Hospital 12  de Octubre, Madrid, Spain. (3)Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. (4)Department of Pharmacology, University of the Basque Country UPV/EHU, Spain, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain. (5)Instituto de Investigación Sanitaria Hospital Universitario de la Princesa and Universidad Autónoma de Madrid, School of Medicine, Madrid, Spain. (6)Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (7)Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany. (8)Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany. (9)Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. (10)Department of Pharmacology, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA. (11)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.

The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor  ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype.

3. Recent Pat CNS Drug Discov. 2016 Jun 19.

Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders.

Ranieri R, Marasco D, Bifulco M, Malfitano AM(1).

Author information:
(1)Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, Baronissi, 84081 Salerno, Italy.

Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant,  specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency. The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models. The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some. In particular, being
the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors. Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases. In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders. Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.

PMID: 27334611

4. Prostate Cancer Prostatic Dis. 2016

The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells.

Morell C(1), Bort A(1), Vara D(2), Ramos-Torres A(1), Rodríguez-Henche N(1),
Díaz-Laviada I(1).

Author information:
(1)Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine, Alcala University, Madrid, Spain. (2)Division of Cell Signalling and
Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.

BACKGROUND: Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer. The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells.

METHODS: NE differentiation of prostate cancer LNCaP cells was induced by serum deprivation or by incubation with interleukin-6, for 6 days. Levels of NE markers and signaling proteins were determined by western blotting. Levels of cannabinoid receptors were determined by quantitative PCR. The involvement of signaling cascades was investigated by pharmacological inhibition and small interfering RNA.

RESULTS: The differentiated LNCaP cells exhibited neurite outgrowth, and increased the expression of the typical NE markers neuron-specific enolase and βIII tubulin (βIII Tub). Treatment with 3 μM WIN inhibited NK differentiation of
LNCaP cells. The cannabinoid WIN downregulated the PI3K/Akt/mTOR signaling pathway, resulting in NE differentiation inhibition. In addition, an activation of AMP-activated protein kinase (AMPK) was observed in WIN-treated cells, which correlated with a decrease in the NE markers expression. Our results also show that during NE differentiation the expression of cannabinoid receptors CB1 and CB2 dramatically decreases.

CONCLUSIONS: Taken together, we demonstrate that PI3K/Akt/AMPK might be an important axis modulating NE differentiation of prostate cancer that is blocked by the cannabinoid WIN, pointing to a therapeutic potential of cannabinoids
against NE prostate cancer.Prostate Cancer and Prostatic Diseases advance online publication, 21 June 2016; doi:10.1038/pcan.2016.19.

5. Cancer Manag Res. 2016 May 12;8:49-55. doi: 10.2147/CMAR.S81425. eCollection 2016.

Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics.

May MB(1), Glode AE(2).

Author information:
(1)Department of Pharmacy, Baptist Health Lexington, Lexington, KY, USA.
(2)Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common symptoms feared by patients, but may be prevented or lessened with appropriate medications. Several antiemetic options exist to manage CINV. Corticosteroids, serotonin receptor antagonists, and neurokinin receptor antagonists are the classes most commonly used in the prevention of CINV. There are many alternative drug classes utilized for the prevention and management of CINV such as
antihistamines, benzodiazepines, anticonvulsants, cannabinoids, and dopamine receptor antagonists. Medications belonging to these classes generally have lower efficacy and are associated with more adverse effects. They are also not as well studied compared to the aforementioned agents. This review will focus on dronabinol, a member of the cannabinoid class, and its role in CINV. Cannabis sativa L. (also known as marijuana) contains naturally occurring
delta-9-tetrahydrocannibinol (delta-9-THC). The synthetic version of delta-9-THC is the active ingredient in dronabinol that makes dronabinol an orally active cannabinoid. Evidence for clinical efficacy of dronabinol will be analyzed in
this review as monotherapy, in combination with ondansetron, and in combination with prochlorperazine.


National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).