CANNABINOIDS AND CANCER NOVIEMBRE 2018

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1. Drugs. 2018 Oct

Medical Use of Cannabinoids.

Fraguas-Sánchez AI(1), Torres-Suárez AI(2)(3).

Author information: 
(1)Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Plaza
Ramón y Cajal s/n, 28040 , Madrid, Spain.
(2)Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Plaza
Ramón y Cajal s/n, 28040 , Madrid, Spain. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..
(3)Institute of Industrial Pharmacy, Complutense University of Madrid, 28040 ,
Madrid, Spain. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

Cannabinoid receptors, endocannabinoids and the enzymes responsible for their
biosynthesis and degradation constitute the endocannabinoid system. In recent
decades, the endocannabinoid system has attracted considerable interest as a
potential therapeutic target in numerous pathological conditions. Its involvement
in several physiological processes is well known, such as in energy balance,
appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and 
vomiting control, memory, learning and immune response, among others, as well as 
in pathological conditions where it exerts a protective role in the development
of certain disorders. As a result, it has been reported that changes in
endocannabinoid levels may be related to neurological diseases such as
Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple
sclerosis, as well as anorexia and irritable bowel syndrome. Alterations in the
endocannabinoid system have also been associated with cancer, affecting the
growth, migration and invasion of some tumours. Cannabinoids have been tested in 
several cancer types, including brain, breast and prostate cancers. Cannabinoids 
have shown promise as analgesics for the treatment of both inflammatory and
neuropathic pain. There is also evidence for a role of the endocannabinoid system
in the control of emotional states, and cannabinoids could prove useful in
decreasing and palliating post-traumatic stress disorder symptoms and anxiolytic 
disorders. The role of the endocannabinoid system in addictions has also been
examined, and cannabinoids have been postulated as alternative and co-adjuvant
treatments in some abuse syndromes, mainly in ethanol and opioid abuses. The
expression of the endocannabinoid system in the eye suggests that it could be a
potential therapeutic target for eye diseases. Considering the importance of the 
endocannabinoid system and the therapeutic potential of cannabinoids in this vast
number of medical conditions, several clinical studies with cannabinoid-based
medications are ongoing. In addition, some cannabinoid-based medications have
already been approved in various countries, including nabilone and dronabinol
capsules for the treatment of nausea and vomiting associated with chemotherapy,
dronabinol capsules for anorexia, an oral solution of dronabinol for both
vomiting associated with chemotherapy and anorexia, a
Δ9-tetrahydrocannabinol/cannabidiol oromucosal spray for pain related to cancer
and for spasticity and pain associated with multiple sclerosis, and an oral
solution of cannabidiol for Dravet and Lennox-Gastaut syndromes. Here, we review 
the available efficacy, safety and tolerability data for cannabinoids in a range 
of medical conditions.



2. Cell Mol Life Sci. 2018 Oct

Cannabinoid exposure during pregnancy and its impact on immune function.

Dong C(1)(2), Chen J(3), Harrington A(4)(2), Vinod KY(5)(6)(7), Hegde ML(8),
Hegde VL(9)(10).

Author information: 
(1)School of Medicine, Medical University of South Carolina, Charleston, SC,
29425, USA.
(2)Department of Chemistry and Biochemistry, College of Arts and Sciences,
University of South Carolina, Columbia, SC, 29208, USA.
(3)Department of Pathology, Microbiology and Immunology, School of Medicine,
University of South Carolina, Columbia, SC, 29208, USA.
(4)School of Pharmacy, Medical University of South Carolina, Charleston, SC,
29425, USA.
(5)Division of Analytical Psychopharmacology, Nathan Kline Institute for
Psychiatric Research, Orangeburg, NY, 10962, USA.
(6)Emotional Brain Institute, Orangeburg, NY, 10962, USA.
(7)Child and Adolescent Psychiatry, New York School of Medicine, New York, NY,
10016, USA.
(8)Department of Radiation Oncology, Institute for Academic Medicine and Research
Institute, The Houston Methodist Research Institute (HMRI), 6550 Fannin St, Smith
08-077, Houston, TX, 77030, USA.
(9)Department of Pathology, Microbiology and Immunology, School of Medicine,
University of South Carolina, Columbia, SC, 29208, USA. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..
(10)Department of Radiation Oncology, Institute for Academic Medicine and
Research Institute, The Houston Methodist Research Institute (HMRI), 6550 Fannin 
St, Smith 08-077, Houston, TX, 77030, USA. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

Cannabinoids are the most commonly abused illicit drugs worldwide. While cannabis
can be beneficial for certain heath conditions, abuse of potent synthetic
cannabinoids has been on the rise. Exposure to cannabinoids is also prevalent in 
women of child-bearing age and pregnant women. These compounds can cross the
placental barrier and directly affect the fetus. They mediate their effects
primarily through G-protein coupled cannabinoid receptors, CB1 and CB2. In
addition to significant neurological effects, cannabinoids can trigger robust
immunomodulation by altering cytokine levels, causing apoptosis of lymphoid cells
and inducing suppressor cells of the immune system. Profound effects of
cannabinoids on the immune system as discussed in this review, suggest that
maternal exposure during pregnancy could lead to dysregulation of innate and
adaptive immune system of developing fetus and offspring potentially leading to
weakening of immune defenses against infections and cancer later in life.
Emerging evidence also indicates the underlying role of epigenetic mechanisms
causing long-lasting impact following cannabinoid exposure in utero.

3. J Control Release. 2018 Oct Synthetic cannabinoids nano-micelles for the management of triple negative breast cancer. Greish K(1), Mathur A(2), Al Zahrani R(2), Elkaissi S(2), Al Jishi M(2), Nazzal O(2), Taha S(2), Pittalà V(3), Taurin S(4). Author information: (1)Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and inherited disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain; Department of oncology, Suez Canal University, Egypt. Electronic address: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.. (2)Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and inherited disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain. (3)Department of Drug Sciences, University of Catania, Catania, Italy. (4)Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and inherited disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain; Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA. Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with poor prognosis and inadequate therapeutic outcome. This contribution reports the use of a cannabinoid derivative, WIN55,212-2 (WIN) on the growth of TNBC in a 4T1 syngeneic mouse model. To reduce the well-known psychoactive side effects of cannabinoids, we prepared a nanomicellar formulation of WIN (SMA-WIN). In vivo biodistribution, in silico ADME predictions, anticancer activity, and psychoactive effect of WIN and SMA-WIN studies suggest that SMA-WIN formulation can reduce to greater extent tumor growth with milder psychoactive side effects when compared to free drug. Finally, the effects of WIN and SMA-WIN in combination with doxorubicin (Doxo), an established chemotherapeutic agent for the treatment of TNBC, were investigated in vitro and in vivo. SMA-WIN in combination with Doxo showed therapeutic efficacy and was able to reduce the tumor volume of TNBC murine model drastically. Moreover, SMA-WIN, while favoring drug tumor accumulation, minimized the adverse psychoactive effects that have impeded the use of this agent in the clinic. To our knowledge, this is the first report for the assessment of cannabinoid nanoparticles in vivo for the treatment of TNBC and its enhanced anticancer effect at low doses with Doxo. These findings suggest a new therapeutic strategy in the management of TNBC. Copyright © 2018 Elsevier B.V. All rights reserved. 4. Arch Toxicol. 2018 Oct 19 Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells. Russo C(1), Ferk F(2), Mišík M(2), Ropek N(2), Nersesyan A(2), Mejri D(2), Holzmann K(2), Lavorgna M(1), Isidori M(1), Knasmüller S(3). Author information: (1)Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università della Campania, L. Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy. (2)Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria. (3)Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria. siegfried.knasmueller@meduniwien.ac.at. Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are consumed in increasing amounts worldwide in cannabis extracts, as they prevent epilepsy, anxiety, and seizures. It was claimed that they may be useful in cancer therapy and have anti-inflammatory properties. Adverse long-term effects of these drugs (induction of cancer and infertility) which are related to damage of the genetic material have not been investigated. Therefore, we studied their DNA-damaging properties in human-derived cell lines under conditions which reflect the exposure of consumers. Both compounds induced DNA damage in single cell gel electrophoresis (SCGE) experiments in a human liver cell line (HepG2) and in buccal-derived cells (TR146) at low levels (≥ 0.2 µM). Results of micronucleus (MN) cytome assays showed that the damage leads to formation of MNi which reflect chromosomal aberrations and leads to nuclear buds and bridges which are a consequence of gene amplifications and dicentric chromosomes. Additional experiments indicate that these effects are caused by oxidative base damage and that liver enzymes (S9) increase the genotoxic activity of both compounds. Our findings show that low concentrations of CBD and CBDV cause damage of the genetic material in human-derived cells. Furthermore, earlier studies showed that they cause chromosomal aberrations and MN in bone marrow of mice. Fixation of damage of the DNA in the form of chromosomal damage is generally considered to be essential in the multistep process of malignancy, therefore the currently available data are indicative for potential carcinogenic properties of the cannabinoids.