Polymeric 3-alkylpyridinium salts (poly-APS) present in the marine spongeReniera sarai show a broad spectrum of biological activities. They are lytic to erythrocytesand various other mammalian cells, enabling the transfection of the latter with alien DNA.Furthermore, they show inhibitory effects to marine bacteria and can inhibit fouling ofmicro- and macroorganisms to submerged surfaces. Finally, poly-APS act as potentcholinesterase inhibitors. The kinetics of acetylcholinesterase inhibition by poly-APS invitro is complex and comprises several successive phases ending in irreversible inhibitionof the enzyme. The latter is accounted for by aggregation and precipitation of the enzyme-inhibitor complexes. Poly-APS are lethal to rats in concentrations above 2.7 mg/kg.Monitoring of the basic vital functions and histopathological analysis showed that theeffects directly ascribable to acetylcholinesterase inhibition are only observed afterapplication of lower concentrations of poly-APS. At higher concentrations, such effectswere masked by other, more pronounced and faster developing lethal effects of the toxin,such as haemolysis and platelet aggregation.

Nicotinic acetylcholine receptors (nAChRs) have long been considered to solely mediate neurotransmission. However, their widespread distribution in the human body suggests a more diverse physiological role. Additionally, the expression of nAChRs is increased in certain cancers, such as lung cancer, and has been associated with cell proliferation, epithelial-to-mesenchymal cell transition, angiogenesis and apoptosis prevention. Several compounds that interact with these receptors have been identified as potential therapeutic agents. They have been tested as drugs for treating nicotine addiction, alcoholism, depression, pain and Alzheimer's disease. This review focuses on nAChR-mediated signalling in cancer, presenting opportunities for the development of innovative nAChR-based anticancer drugs. It displays the differences in expression of each nAChR subunit between normal and cancer cells for selected cancer types, highlighting their possible involvement in specific cases. Antagonists of nAChRs that could complement existing cancer therapies are summarised and critically discussed. We hope that this review will stimulate further research on the role of nAChRs in cancer potentially leading to innovative cancer therapies.

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.

We report on screening tests of 66 extracts obtained from 35 marine sponge species from the Caribbean Sea (Curaçao) and from eight species from the Great Barrier Reef (Lizard Island). Extracts were prepared in aqueous and organic solvents and were tested for hemolytic, hemagglutinating, antibacterial and anti-acetylcholinesterase (AChE) activities, as well as their ability to inhibit or activate cell protein phosphatase 1 (PP1). The most interesting activities were obtained from extracts of Ircinia felix, Pandaros acanthifolium, Topsentia ophiraphidites, Verongula rigida and Neofibularia nolitangere. Aqueous and organic extracts of I. felix and V. rigida showed strong antibacterial activity. Topsentia aqueous and some organic extracts were strongly hemolytic, as were all organic extracts from I. felix. The strongest hemolytic activity was observed in aqueous extracts from P. acanthifolium. Organic extracts of N. nolitangere and I. felix inhibited PP1. The aqueous extract from Myrmekioderma styx possessed the strongest hemagglutinating activity, whilst AChE inhibiting activity was found only in a few sponges and was generally weak, except in the methanolic extract of T. ophiraphidites.

We report on the screening of ethanolic extracts from 33 deep-sea Antarctic marine sponges for different biological activities. We monitored hemolysis, inhibition of acetylcholinesterase, cytotoxicity towards normal and transformed cells and growth inhibition of laboratory, commensal and clinically and ecologically relevant bacteria. The most prominent activities were associated with the extracts from sponges belonging to the genus Latrunculia, which show all of these activities. While most of these activities are associated to already known secondary metabolites, the extremely strong acetylcholinesterase inhibitory potential appears to be related to a compound unknown to date. Extracts from Tetilla leptoderma, Bathydorus cf. spinosus, Xestospongia sp., Rossella sp., Rossella cf. racovitzae and Halichondria osculum were hemolytic, with the last two also showing moderate cytotoxic potential. The antibacterial tests showed significantly greater activities of the extracts of these Antarctic sponges towards ecologically relevant bacteria from sea water and from Arctic ice. This indicates their ecological relevance for inhibition of bacterial microfouling.

Polymeric alkylpyridinium salts (poly-APS) isolated from the Mediterranean marine sponge, Haliclona (Rhizoniera) sarai, effectively inhibit barnacle larva settlement and natural marine biofilm formation through a non-toxic and reversible mechanism. Potential use of poly-APS-like compounds as antifouling agents led to the chemical synthesis of monomeric and oligomeric 3-alkylpyridinium analogues. However, these are less efficient in settlement assays and have greater toxicity than the natural polymers. Recently, a new chemical synthesis method enabled the production of poly-APS analogues with antibacterial, antifungal and anti-acetylcholinesterase activities. The present study examines the antifouling properties and toxicity of six of these synthetic poly-APS using the barnacle (Amphibalanus amphitrite) as a model (cyprids and II stage nauplii larvae) in settlement, acute and sub-acute toxicity assays. Two compounds, APS8 and APS12-3, show antifouling effects very similar to natural poly-APS, with an anti-settlement effective concentration that inhibits 50% of the cyprid population settlement (EC₅₀) after 24 h of 0.32 mg/L and 0.89 mg/L, respectively. The toxicity of APS8 is negligible, while APS12-3 is three-fold more toxic (24-h LC₅₀: nauplii, 11.60 mg/L; cyprids, 61.13 mg/L) than natural poly-APS. This toxicity of APS12-3 towards nauplii is, however, 60-fold and 1200-fold lower than that of the common co-biocides, Zn- and Cu-pyrithione, respectively. Additionally, exposure to APS12-3 for 24 and 48 h inhibits the naupliar swimming ability with respective IC₅₀ of 4.83 and 1.86 mg/L.