GPR55 Receptor Activation by the N-acyl Dopamine Family Lipids Induces Apoptosis in Cancer Cells via the Nitric Oxide Synthase (nNOS) Over-Stimulation

Autor: Polina V Dudina, Alina M. Gamisonia, Anastasia A Gaydaryova, M. G. Akimov, G. N. Zinchenko, Andrey S. Kuznetsov, Vladimir V. Bezuglov, Natalia Gretskaya
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cannabinoid receptor
Dopamine
N-acyldopamines
Enzyme Activators
Antineoplastic Agents
Apoptosis
Nitric Oxide Synthase Type I
PC12 Cells
Article
Catalysis
lcsh:Chemistry
Inorganic Chemistry
chemistry.chemical_compound
Cell Line
Tumor
Neoplasms
Animals
Humans
cancer cell apoptosis
N-acyldopamines cytotoxicity
Physical and Theoretical Chemistry
endocannabinoids
Receptors
Cannabinoid
lcsh:QH301-705.5
Molecular Biology
Spectroscopy
Cannabinoid Receptor Agonists
nitric oxide synthase
Fatty Acids
Organic Chemistry
General Medicine
Anandamide
Endocannabinoid system
Rats
Computer Science Applications
Cell biology
Molecular Docking Simulation
Intracellular signal transduction
lcsh:Biology (General)
lcsh:QD1-999
chemistry
GPR55
Cancer cell
Lysophosphatidylinositol
lipids (amino acids
peptides
and proteins)
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 2
International Journal of Molecular Sciences, Vol 22, Iss 622, p 622 (2021)
ISSN: 1422-0067
DOI: 10.3390/ijms22020622
Popis: GPR55 is a GPCR of the non-CB1/CB2 cannabinoid receptor family, which is activated by lysophosphatidylinositol (LPI) and stimulates the proliferation of cancer cells. Anandamide, a bioactive lipid endocannabinoid, acts as a biased agonist of GPR55 and induces cancer cell death, but is unstable and psychoactive. We hypothesized that other endocannabinoids and structurally similar compounds, which are more hydrolytically stable, could also induce cancer cell death via GPR55 activation. We chemically synthesized and tested a set of fatty acid amides and esters for cell death induction via GPR55 activation. The most active compounds appeared to be N-acyl dopamines, especially N-docosahexaenoyl dopamine (DHA-DA). Using a panel of cancer cell lines and a set of receptor and intracellular signal transduction machinery inhibitors together with cell viability, Ca2+, NO, ROS (reactive oxygen species) and gene expression measurement, we showed for the first time that for these compounds, the mechanism of cell death induction differed from that published for anandamide and included neuronal nitric oxide synthase (nNOS) overstimulation with concomitant oxidative stress induction. The combination of DHA-DA with LPI, which normally stimulates cancer proliferation and is increased in cancer setting, had an increased cytotoxicity for the cancer cells indicating a therapeutic potential.
Databáze: OpenAIRE
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