Apoptotično delovanje alkilpiridinijevih spojin na celice pljučnega adenokarcinoma (Slovene)

Alkylpyridinium polymers (polyAPS) are natural products isolated from the Mediterranean species of marine sponge Reniera sarai. At first, these compounds were recognized as acetylcholinesterase (AChE) inhibitors, but preliminary experiments with their synthetic analogues have revealed they are much stronger antagonists of ?7 nicotinic acetylcholine receptors (nAChRs). Natural polyAPS are cytotoxic for a non-small cell lung cancer (NSCLC) adenocarcinoma cell line (A549), but not for normal lung fibroblasts that do not express ?7 or other nAChR subtypes, which are less susceptible to polyAPS. Preliminary experiments also revealed the cytotoxic effects of polyAPS on a lung adenocarcinoma primary cell line as well as their ability to limit the growth of solid tumors in mice. However, serious drawbacks of the polyAPS compounds include their large, heterogeneous molecular size, their propensity to form even larger supramolecular aggregates in aqueous solutions and their non-specific cytolytic activity. Therefore a therapeutic use of these natural products seems unlikely. Recently, we prepared a series of smaller synthetic alkylpyridinium oligomers with similar structural and functional properties. Each has a defined molecular weight and is not prone to aggregate in aqueous solutions. Initial experiments have shown that at least one analogue (8Br-1) is very potent ?7 nAChR antagonist at pM concentrations. This concentration is several orders of magnitude lower than is required for AChE inhibition. This finding is important since AChE inhibition might enhance cancer cell proliferation, which would oppose the effects of nAChR antagonists that reduce proliferation of NSCLC, SCLC and MPM (mezothelioma) lung cancer cell lines. The ?7 nAChR also is important for mediating cognitive functions in the central nervous system, protected by the blood brain barrier. In nonneural cells expressing nAChRs, binding of the agonist nicotine triggers antiapoptotic and proliferative signaling pathways which prevent cell death and enhance tumor growth. By using nAChR antagonists, we would like to achieve the opposite effect: to activate proapoptotic pathways that lead to cell death and destruction of cancer cells and inhibit their proliferation. We believe that the smaller, synthetic alkypyridinium analogs, due to their high affinity for ?7 nAChRs, may become useful drugs in treating one of the most common types of lung cancer connected with smoking. These compounds may also serve as tools to elucidate certain signaling pathways and the roles of proapoptotic proteins involved in mitochondrial damage and activation of caspases. Our in vitro studies will provide a solid foundation for our subsequent tests of these compounds in animal models of these cancers.

Lung cancer remains one of the most invasive cancers and cause high percent of death among patients with cancer. most of the lung cancer forms are tightly linked to smoking. Knowledge about different cancer cells, their receptors and signaling pathways, which prevent apoptosis, enhance proliferation and angiogenesis is basic key leading to the development of suitable compounds, which would be effective for certain lung cancer types. Results and publication raised from our project work we contributed to the knowledge of mechanisms, which prevent cancer cells to become apoptotic. We revealed the role of nicotine and nAChR and also showed how natural or synthetic nAChR antagonists, above all those which are specific for alpha 7 subtype, trigger signaling pathways which cause programmed cell death in cancer cells, while normal cells remain largely unaffected. Experiments in vivo using imunononcompetent mice showed that direct intra tumor injection of one of the alkylpyridinium analogues strongly decrease or even completely stop or eliminate human adenocarcinoma tumors in experimental animals.

It is hard to define how our research contributes to the development of Slovenia. Our answer is no more or no less than it contributes to the science in general. We can only say that many different aspects of of lung cancer, its treatment and a fact that different lung cancer subtypes are tightly linked to smoking is not only a Slovenian but a worldwide problem. Domestic knowledge about this phenomena, mechanisms involved in programmed cell death, proliferation of cancer cells and angiogenesis is with no doubt important not only for Slovenia but in much broader context. In this regard our research of lung cancer also contributes to the recognition of Slovenia and its science.