Effects of the anthelmintic drug PF1022A on mammalian tissue and cells.

Nematode infections cause human morbidity and enormous economic loss in livestock. Since resistance against currently available anthelmintics is a worldwide problem, there is a continuous need for new compounds. The cyclooctadepsipeptide PF1022A is a novel anthelmintic that binds to the latrophilin-like transmembrane receptor important for pharyngeal pumping in nematodes. Furthermore, PF1022A binds to GABA receptors, which might contribute to the anthelmintic effect. Like other cyclodepsipeptides, PF1022A acts as an ionophore. However, no correlation between ionophoric activity and anthelmintic properties was found. This is the first study describing the effect of PF1022A on mammalian cells and tissues. While channel-forming activity was observed already at very low concentrations, changes in intracellular ion concentrations and reduction of contractility in isolated guinea pig ileum occurred at multiples of anthelmintically active concentrations. PF1022A did not induce necrotic cell death indicated by complete lack of cellular lactate dehydrogenase release. In contrast, apoptosis induction via the mitochondrial pathway was suggested for long-term drug treatment at high concentrations due to numerous apoptotic morphological changes as well as mitochondrial membrane depolarisation. Short time effects were based on cell cycle blockade in G(0)/G(1) phase. Additionally, the cell cycle and apoptosis regulating proteins p53, p21 and bax, but not Bcl-2 were shown to impact on PF1022A-induced cytotoxicity. However, since PF1022A-induced cytotoxicity was found at drug concentrations higher than those used in anthelmintic treatment, it can be suggested that PF1022A intake might not impair human or animal health. Thus, PF1022A seems to be a safe alternative to other anthelmintic drugs.

Cyclodepsipeptides - potential drugs and lead compounds in the drug development process.

Cyclodepsipeptides show an interesting spectrum of biological activity. Members of this new class of potential drugs may also serve as lead compounds for more pharmacologically potent and toxicologically safe derivatives. Some of these natural products and (semi-)synthetic derivatives have already been evaluated in clinical trials. A common feature of cyclodepsipeptides is their ionophoric properties. However, their pharmacologically relevant action does not seem to correlate with this feature; rather it is based on interactions with distinct cellular compartments and signal transduction pathways. Cyclodepsipeptides, which are currently being evaluated in clinical trials, are used in refractory cancer therapy, usually in combination with other cytotoxic drugs. A series of cyclooctadepsipeptides, however, shows a completely different spectrum of biological activity, namely, potent anthelmintic properties. A number of cyclodepsipeptides have been well characterized in vitro and in vivo, and interesting modes of action, such as antiplasmodial, antiviral, insecticidal, cytotoxic, and antiproliferative properties have been observed. Whether these natural products will be of benefit for patients must be evaluated in clinical trials. Recently, a number of cyclodepsipeptides from marine sponges, bacteria and fungi have been identified. Subsequent structural determination revealed unique structural features within some of these compounds. It was suggested that the cyclic depsipeptide structure is important for the biological activity because the linear homologues were inactive. The scope of activity of these newly isolated natural products spans a range from cytoprotective activity against HIV-1 infection, growth inhibitory effects toward cancer cells, and antimycobacterial, and antimalarial activity.

Effects of moniliformin in presence of cyclohexadepsipeptides on isolated mammalian tissue and cells.

Secondary metabolites produced by Fusarium spp. including beauvericin, enniatin and moniliformin are mycotoxins identified in cereal samples. The two cyclohexadepsipeptide mycotoxins beauvericin and enniatin have cytotoxic, antibiotic, insecticidal and ionophoric properties, while moniliformin primarily acts as a cardiotoxic mycotoxin. In this study, we examined the electromechanical and electrophysiological effects of moniliformin and moniliformin with ionophoric mycotoxins on cells (ventricular myocytes, Caco-2 cells) and in multicellular preparations (papillary muscles and terminal ilea of the guinea pig). Additionally, we investigated the influence of moniliformin on cell homeostasis in absence and presence of the cyclodepsipeptide mycotoxins (ventricular myocytes, Caco-2 cells). Experiments were performed using isometric measurements of contractility, intracellular microelectrode and patch-clamp techniques, and fluorescence imaging. While ionophoric cyclohexadepsipeptides affect action potential parameters and cell homeostasis, moniliformin did not change spontaneous rates of activity or cardiac action potentials. Furthermore, moniliformin had no effect on intracellular concentrations of ions and ATP, and did not affect pH. Moniliformin reduced contractility in papillary muscle, terminal ileum, the aorta and the pulmonary artery. However, moniliformin did not alter beauvericin and enniatin induced effects. From our studies, we conclude that moniliformin is not solely a cardiotoxic secondary metabolite, but also exerts its effects on smooth muscle. Moreover, there is no synergistic relationship between moniliformin and the concurrently produced cyclohexadepsipeptide mycotoxins beauvericin and enniatin.