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1.
Int J Mol Sci ; 24(6)2023 Mar 14.
Article in English | MEDLINE | ID: mdl-36982628

ABSTRACT

GPR55 is a non-canonical cannabinoid receptor, important for cancer proliferation. Depending on the ligand, it induces either cell proliferation or death. The objective of the study was to establish the mechanisms of this multidirectional signaling. Using the CRISPR-Cas9 system, the GPR55, CB1, CB2, and GPR18 receptor knockouts of the MDA-MB-231 line were obtained. After the CB2 receptor knockout, the pro-apoptotic activity of the pro-apoptotic ligand docosahexaenoyl dopamine (DHA-DA) slightly increased, while the pro-proliferative activity of the most active synthetic ligand of the GPR55 receptor (ML-184) completely disappeared. On the original cell line, the stimulatory effect of ML-184 was removed by the CB2 receptor blocker and by GPR55 receptor knockout. Thus, it can be confidently assumed that when proliferation is stimulated with the participation of the GPR55 receptor, a signal is transmitted from the CB2 receptor to the GPR55 receptor due to the formation of a heterodimer. GPR18 was additionally involved in the implementation of the pro-apoptotic effect of DHA-DA, while the CB1 receptor is not involved. In the implementation of the pro-apoptotic action of DHA-DA, the elimination of Gα13 led to a decrease in cytotoxicity. The obtained data provide novel details to the mechanism of the pro-proliferative action of GPR55.


Subject(s)
Neoplasms , Receptor, Cannabinoid, CB2 , Receptor, Cannabinoid, CB2/genetics , Ligands , Receptors, Cannabinoid/metabolism , Signal Transduction , Cell Proliferation , Apoptosis , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptor, Cannabinoid, CB1 , Neoplasms/genetics
2.
Molecules ; 26(7)2021 Mar 26.
Article in English | MEDLINE | ID: mdl-33810344

ABSTRACT

Stabilized melanocortin analog peptide ACTH(6-9)PGP (HFRWPGP) possesses a wide range of neuroprotective activities. However, its mechanism of action remains poorly understood. In this paper, we present a study of the proproliferative and cytoprotective activity of the adrenocorticotropic hormone fragment 6-9 (HFRW) linked with the peptide prolyine-glycyl-proline on the SH-SY5Y cells in the model of oxidative stress-related toxicity. The peptide dose-dependently protected cells from H2O2, tert-butyl hydroperoxide, and KCN and demonstrated proproliferative activity. The mechanism of its action was the modulation of proliferation-related NF-κB genes and stimulation of prosurvival NRF2-gene-related pathway, as well as a decrease in apoptosis.


Subject(s)
Adrenocorticotropic Hormone/pharmacology , Antioxidants/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Oligopeptides/pharmacology , Oxidative Stress/drug effects , Proline/analogs & derivatives , Cell Line, Tumor , Humans , Hydrogen Peroxide/toxicity , Neuroprotective Agents/pharmacology , Proline/pharmacology , Reactive Oxygen Species/metabolism
3.
Int J Mol Sci ; 22(2)2021 Jan 09.
Article in English | MEDLINE | ID: mdl-33435517

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Cannabinoid Receptor Agonists/pharmacology , Dopamine/analogs & derivatives , Enzyme Activators/pharmacology , Nitric Oxide Synthase Type I/metabolism , Receptors, Cannabinoid/metabolism , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cannabinoid Receptor Agonists/chemistry , Cell Line, Tumor , Dopamine/chemistry , Dopamine/pharmacology , Enzyme Activators/chemistry , Fatty Acids/chemistry , Fatty Acids/pharmacology , Humans , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , PC12 Cells , Rats
4.
Eur J Pharmacol ; 883: 173346, 2020 Sep 15.
Article in English | MEDLINE | ID: mdl-32659303

ABSTRACT

Glioblastoma (GBM) is an aggressive and lethal form of brain cancer with a high invasion capacity and a lack of effective chemotherapeutics. Retinoid bexarotene (BXR) inhibits the neurospheroidal colony formation and migration of primary glioblastoma cells but has side effects. To enhance the BXR glioblastoma selectivity and cytotoxicity, we chemically modified it at the carboxyl group with either nitroethanolamine (NEA) bearing a NO-donating group (a well-known bioactivity enhancer; BXR-NEA) or with a dopamine (DA) moiety (to represent the highly toxic for various tumor cells N-acyldopamine family; BXR-DA). These two novel compounds were tested in the 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Both BXR-DA and BXR-NEA were found to be more toxic for rat C6 and human U-87MG glioma cells than the initial BXR. After 24 h incubation of the cells (monolayer culture) with the drugs, the IC50 values were in the range of 28-42, and 122-152 µM for BXR derivatives and BXR, respectively. The cell death occurred via apoptosis according to the annexin staining and caspase activation. The tumor spheroids demonstrated higher resistance to the treatment compared to that one of the monolayer cultures. BXR-DA and BXR-NEA were more specific against tumor cells than the parental drug, in particular the selectivity index was 1.8-2.7 vs. 1.3-1.5, respectively. Moreover, they inhibited cell migration more effectively than parental BXR according to a scratch assay. Cell spreading from the tumor spheroids was also inhibited. Thus, the obtained BXR derivatives could be promising for glioblastoma treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Bexarotene/pharmacology , Brain Neoplasms/drug therapy , Glioma/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Bexarotene/analogs & derivatives , Bexarotene/chemical synthesis , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Culture Techniques , Cell Line, Tumor , Cell Movement/drug effects , Dose-Response Relationship, Drug , Glioma/metabolism , Glioma/pathology , Humans , Inhibitory Concentration 50 , Molecular Structure , Neoplasm Invasiveness , Rats , Spheroids, Cellular , Structure-Activity Relationship
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