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Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. (Jacobsson)
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
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2013 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 87, no 11, 1939-1951 p.Article in journal (Refereed) Published
Abstract [en]

Compounds acting on the cannabinoid (CB) receptors are involved in the control of cell fate, and there is an emerging consensus that CBs have anticancer effects. However, the CB-mediated effects are contradictory since some studies suggest stimulatory effects on cancer cell proliferation, and CBs have been shown to stimulate both proliferation and differentiation of other mitotic cells such as stem and progenitor cells. In this study, the concentration-dependent effects of synthetic and endogenous CBs on the viability of mouse P19 embryonal carcinoma (EC) cells have been examined by using fluorescence assays of cell membrane integrity, cell proliferation, oxidative stress, and detection of apoptosis and necrosis. All compounds examined produced a concentration-dependent decrease in cell viability in the micromolar range, with the potent CB receptor agonist HU 210 and the enantiomer HU 211(with no CB receptor activity) being the most potent compounds examined with apparent IC50 values of 1 µM and 0.6 µM, respectively. The endogenous CB anandamide showed similar potency and efficacy as structurally related polyunsaturated fatty acids with no reported activity at the CB receptors. The rapid (within hours) decrease in cell viability induced by the examined CBs suggests cytocidal rather than antiproliferative effects, and is dependent on the plating cell population density with the highest toxicity around 100 cells/mm2. The CB-induced cytotoxicity, that appears to involve CB receptors and the sphingomyelin-ceramide pathway, is a mixture of both apoptosis and necrosis that can be blocked by the antioxidants α-tocopherol and N-acetylcysteine. In conclusion, both synthetic and endogenous CBs, produce seemingly unspecific cytotoxic effects in the P19 EC cells.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2013. Vol. 87, no 11, 1939-1951 p.
Keyword [en]
cannabinoids, polyunsaturated fatty acids, embryonal carcinoma cells, cytotoxicity, oxidative stress
National Category
Pharmacology and Toxicology
Research subject
biokemisk farmakologi
URN: urn:nbn:se:umu:diva-51550DOI: 10.1007/s00204-013-1051-3ISI: 000325700300005OAI: diva2:484041
Available from: 2012-01-31 Created: 2012-01-26 Last updated: 2014-02-28Bibliographically approved
In thesis
1. Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development
Open this publication in new window or tab >>Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Effekter av cannabinoider på cancerceller, neuronal differentiering och embryonal utveckling
Abstract [en]

Cannabinoids (CBs) are compounds that activate the CB1 and CB2 receptors. CB receptors mediate many different physiological functions, and cannabinoids have been reported to decrease tumor cell viability, proliferation, migration, as well as to modulate metastasis.

In this thesis, the effects of cannabinoids on human colorectal carcinoma Caco-2 cells (Paper I) and mouse P19 embryonal carcinoma (EC) cells (Paper III) were studied.  In both cell lines, the compounds examined produced a concentration- and time-dependent decrease in cell viability. In Caco-2-cells, HU 210 and the pyrimidine antagonist 5-fluorouracil produced synergistic effects upon cell viability. The mechanisms behind the cytocidal effects of cannabinoids appear to be mediated by other than solely the CB receptor, and a common mechanism in Caco-2 and P19 EC cells was oxidative stress. However, in P19 EC cells the CB receptors contribute to the cytocidal effects possibly via ceramide production.

In paper II, the association between CB1 receptor immunoreactivity (CB1IR) and different histopathological variables and disease-specific survival of colorectal cancer (CRC) was investigated. In microsatellite stable (MSS) cases there was a significant positive association of the tumor grade with the CB1IR intensity. A high CB1IR is indicative of a poorer prognosis in MSS with stage II CRC patients.

Paper IV focused on the cytotoxic effects of cannabinoids during neuronal differentiation. HU 210 affected the cell viability, neurite formation and produced a decreased intracellular AChE activity. The effects of cannabinoids on embryonic development and survival were examined in Paper V, by repeated injection of cannabinoids in fertilized chicken eggs. After 10 days of incubation, HU 210 and cannabidiol (without CB receptor affinity), decreased the viability of chick embryos, in a manner that could be blocked by α-tocopherol (antioxidant) and attenuated by AM251 (CB1 receptor antagonist).

In conclusion, based on these studies, the cannabinoid system may provide a new target for the development of drugs to treat cancer such as CRC. However, the CBs also produce seemingly unspecific cytotoxic effects, and may have negative effects on the neuronal differentiation process. This may be responsible for, at least some of, the embryotoxic effects found in ovo, but also for the cognitive and neurotoxic effects of cannabinoids in the developing and adult nervous system.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 48 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1474
Cannabinoids, cell viability, neuronal differentiation, colorectal cancer, chick embryo
National Category
Pharmacology and Toxicology
Research subject
biokemisk farmakologi; Toxicology
urn:nbn:se:umu:diva-51560 (URN)978-91-7459-358-7 (ISBN)
Public defence
2012-02-24, Sal E04, by 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Available from: 2012-02-03 Created: 2012-01-26 Last updated: 2012-02-27Bibliographically approved

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Gustafsson, SofiaWallenius, AndersZackrisson, HPopova, DinaPlym Forshell, LinusJacobsson, Stig OP
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