Naslov
New perspectives for cholinesterase-based ligands research

Autori
Katalinić, Maja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of Abstracts of the Epigenetics and Male Reproductive Health Symposium 2023 / - , 2023, 19-19

Skup
Epigenetics and Male Reproductive Health Symposium

Mjesto i datum
Zagreb, Hrvatska, 29.03.2023

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Podatak o recenziji nije dostupan

Ključne riječi
cytotoxicity ; cancer ; apoptotis ; caspase ; oximes

Sažetak
Compounds interacting reversibly with acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8), two important enzymes in the neurotransmission, have been designed and synthesised for the last 70 years. The main purpose of such compounds is either to reversibly inhibit these enzymes as a therapy for several nerve-related disorders and conditions (like Alzheimer’s disease and myasthenia gravis), or to reactivate their activity upon covalent inhibition by deadly organophosphorus (OP) agents. Combination of the specific structural requirements needed to fit the cholinesterases’ active site, together with the motifs ensuring desired biochemical properties, created an outstanding compounds and scaffolds library unfortunately unexplored beyond the main scope of action. During the studies within the project CellToxTargets financed by the Croatian Science Foundation, we have observed that selected cholinesterase-based ligands have a cytotoxic effect on different cell types. Results showed that some compounds caused time-dependent toxicity accompanied by increased induction of ROS and mitochondrial membrane potential dysfunction, which leads to disruption of oxidative phosphorylation chain that maintains adenosine triphosphate (ATP) energy levels. Also, some compounds activated specific caspase 8 and 9 enzymes responsible for initiating the apoptosis process, either through the extrinsic or intrinsic pathway. This led us to conclude that such effects come either from interactions with one of the cell-surface receptors or by a direct binding to some intracellular target, perhaps on mitochondria, upon entering the cell by any transport mechanism. According to the results, compounds that were toxic to neuroblastoma (SH-SY5Y) and hepatocytoma (HepG2) cells were also toxic to breast cancer cells (MDA-MB-231) and prostate cancer cells (PC3). This may suggest that their putative mechanism of action is the same, which indicates potential antitumour activity of these compounds worth further investigation. This research was supported by the Croatian Science Foundation, grant number HrZZ-UIP2017-05- 7260.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

POVEZANOST RADA