20.500.12556/RUL-132067 APS8 delays tumor growth in mice by inducing apoptosis of lung adenocarcinoma cells expressing high number of α7 nicotinic receptors The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung cancer, we determined its systemic and organ-specific toxicity in mice, evaluated its antitumor activity against adenocarcinoma xenograft models, and examined the in-vitro mechanisms of APS8 in terms of apoptosis, cytotoxicity, and viability. We also measured Ca$^{2+}$ influx into cells, and evaluated the effects of APS8 on Ca$^{2+}$ uptake while siRNA silencing of the gene for α7 nAChRs, CHRNA7. APS8 was not toxic to mice up to 5 mg/kg i.v., and no significant histological changes were observed in mice that survived APS8 treatment. Repetitive intratumoral injections of APS8 (4 mg/kg) significantly delayed growth of A549 cell tumors, and generally prevented regrowth of tumors, but were less effective in reducing growth of HT29 cell tumors. APS8 impaired the viability of A549 cells in a dose-dependent manner and induced apoptosis at micro molar concentrations. Nano molar APS8 caused minor cytotoxic effects, while cell lysis occurred at APS8 >3 µM. Furthermore, Ca$^{2+}$ uptake was significantly reduced in APS8-treated A549 cells. Observed differences in response to APS8 can be attributed to the number of α7 nAChRs expressed in these cells, with those with more AChRs (i.e., A549 cells) being more sensitive to nAChR antagonists like APS8. We conclude that α7 nAChR antagonists like APS8 have potential to be used as therapeutics for tumors expressing large numbers of α7 nAChRs. lung cancer antitumor activity A549 HT29 CHRNA7 alkylpiridinium SCID mice toxicity apoptosis lung neoplasms therapy nicotinic receptors true false true Angleški jezik Ni določen Članek v reviji 2021-10-11 11:32:27 2021-10-11 11:32:29 2022-09-12 04:10:53 0000-00-00 00:00:00 2018 0 0 17 str. iss. 10, art. 367 Vol. 16 2018 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577.1 1660-3397 10.3390/md16100367 4683642 RAZ_Berne_Sabina_2018.pdf RAZ_Berne_Sabina_2018.pdf 1 82D9A7BF7CE28A6F22ED41CB6A446070 f3823f290dc014b01b17ff150e82b6a0ff84b982dcad2e19470a431076d9bfae 30715a3a-2a76-11ec-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=149572 https://www.mdpi.com/1660-3397/16/10/367 1 da642f3f-2a75-11ec-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=149571 Biotehniška fakulteta Veterinarska fakulteta 0 0 0