Vpliv izbranih prostih in v nanodelce vgrajenih antagonistov nikotinskih acetilholinskih receptorjev na celice raka pljučJoukhan, Ahmad (Avtor) Drobne, Damjana (Mentor) Sollner Dolenc, Marija (Komentor) marine toxinsnicotinic acetylcholine receptorsnAChR antagonists3-alkylpyridinium saltschemotherapeutic agentsThe overexpression of nicotinic acetylcholine receptors (nAChRs), particularly ?7-nAChR, in lung cancer cells facilitates the binding of nicotine or other nAChR agonists such as nicotine metabolites or acetylcholine. The binding and activation of these receptors not only promote tumor growth but also enhance cancer resistance to chemotherapy. This study investigated the efficacy of various nAChR antagonists (APS7-2, APS12-2 and APS8-2) in attenuation of the nicotine effects on A549 lung cancer cells. APS7-2, APS8-2, and APS12-2 are synthetic analogs of the marine sponge toxin 3-alkylpyridinium salts (poly-APS). APS12-2 acts as a ?12ß1?? nAChR antagonist, while our electrophysiological experiments demonstrated that APS7-2 and APS8-2 function as ?7-nAChR antagonists. We also investigated the potential of APS12-3, another poly-APS analog, to attenuate nicotine effects on A549 cancer cells. APS8-2 did not exhibit cytotoxicity on A549 cells, whereas APS7-2, APS12-2, and APS12-3 demonstrated cytotoxicity. The effects of nicotine on A549 cells include heightened cell viability and proliferation, elevated levels of Ca2+, and diminished production of reactive oxygen species (ROS) induced by cisplatin. These effects were attenuated by APS8-2, APS12-2, and APS12-3, while APS7-2 was less effective. APS12-2-loaded gelatin nanoparticles (APS12-2-loaded GNPs) were prepared using the nanoprecipitation technique, and their cytotoxic effects were assessed on A549 cells and BEAS-2B non-tumorigenic lung cells. The cytotoxicity of APS12-2 on BEAS-2B cells was significantly reduced when APS12-2 was loaded into GNPs, whereas the cytotoxicity on A549 cells was only slightly decreased. The potential of APS12-2 and APS12-2-loaded GNPs was also investigated on nicotine-induced reduction in cisplatin efficacy. Nicotine reduced the cytotoxicity, formation of ROS, and lipid droplet formation induced by cisplatin in A549 cells. APS12-2 and APS12-2-loaded GNPs attenuated the nicotine-induced reduction in the efficacy of cisplatin. Our findings indicate that both APS12-2 and APS12-2-loaded GNPs hold promise as supportive agents in chemotherapeutic cisplatin for lung cancer.20242024-09-13 07:15:07Doktorsko delo/naloga161633sl