Abstract
Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results. Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist.
Highlights
Cannabinoid receptors (CBRs) are specific targets for endogenous and exogenous cannabinoids
Based on our previous studies on 2-oxo-1,8-naphthyridine-3-carboxamide derivatives [27], it is reasonable to assume that LV50 behaves as a CB2 receptor (CB2R) agonist
CB2R has been found in many types of cancer cells, including human leukemia and lymphoma cell lines
Summary
Cannabinoid receptors (CBRs) are specific targets for endogenous and exogenous cannabinoids. Behavioral, electrophysiological, and neurochemical studies support a role for CB2R activation in modulating inflammatory nociception, beside the palliative actions of cannabinoids, various in vitro studies and animal models have shown that activation of the CB2R induces apoptosis or cell cycle arrest and inhibits neo-angiogenesis, inhibiting tumor growth [6,7,8,9,10]. On this regard, it is well known that survival signaling pathways including extracellular signal-regulated kinase (ERK) [11], c-Jun-NH2-kinase [12], p38 mitogen-activated protein kinase (MAPK) [13], and the ceramide pathway [14] can be regulated through CBR activation. The cell cycle arrest is followed by apoptotic death and activation of the transcription factor JunD is essential for these actions [15,16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
