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APS8, a Polymeric Alkylpyridinium Salt Blocks α7 nAChR and Induces Apoptosis in Non-Small Cell Lung Carcinoma
Department of Biology, Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, 17176 Stockholm, Sweden
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Epidemiology, Biostatistics and Clinical Trials, IRCCS A.O.U. S. Martino-IST, National Institute for Cancer Research, 16132 Genoa, Italy
* Author to whom correspondence should be addressed.
Received: 9 April 2013; in revised form: 17 June 2013 / Accepted: 25 June 2013 / Published: 16 July 2013
Abstract: Naturally occurring 3-alkylpyridinium polymers (poly-APS) from the marine sponge Reniera sarai, consisting of monomers containing polar pyridinium and nonpolar alkyl chain moieties, have been demonstrated to exert a wide range of biological activities, including a selective cytotoxicity against non-small cell lung cancer (NSCLC) cells. APS8, an analog of poly-APS with defined alkyl chain length and molecular size, non-competitively inhibits α7 nicotinic acetylcholine receptors (nAChRs) at nanomolar concentrations that are too low to be acetylcholinesterase (AChE) inhibitory or generally cytotoxic. In the present study we show that APS8 inhibits NSCLC tumor cell growth and activates apoptotic pathways. APS8 was not toxic for normal lung fibroblasts. Furthermore, in NSCLC cells, APS8 reduced the adverse anti-apoptotic, proliferative effects of nicotine. Our results suggest that APS8 or similar compounds might be considered as lead compounds to develop antitumor therapeutic agents for at least certain types of lung cancer.
Keywords: 3-alkylpyridinium polymers; apoptosis; nicotine; nicotinic acetylcholine receptor; non-small cell lung carcinoma
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Zovko, A.; Viktorsson, K.; Lewensohn, R.; Kološa, K.; Filipič, M.; Xing, H.; Kem, W.R.; Paleari, L.; Turk, T. APS8, a Polymeric Alkylpyridinium Salt Blocks α7 nAChR and Induces Apoptosis in Non-Small Cell Lung Carcinoma. Mar. Drugs 2013, 11, 2574-2594.
Zovko A, Viktorsson K, Lewensohn R, Kološa K, Filipič M, Xing H, Kem WR, Paleari L, Turk T. APS8, a Polymeric Alkylpyridinium Salt Blocks α7 nAChR and Induces Apoptosis in Non-Small Cell Lung Carcinoma. Marine Drugs. 2013; 11(7):2574-2594.
Zovko, Ana; Viktorsson, Kristina; Lewensohn, Rolf; Kološa, Katja; Filipič, Metka; Xing, Hong; Kem, William R.; Paleari, Laura; Turk, Tom. 2013. "APS8, a Polymeric Alkylpyridinium Salt Blocks α7 nAChR and Induces Apoptosis in Non-Small Cell Lung Carcinoma." Mar. Drugs 11, no. 7: 2574-2594.