Identification of a Novel Topoisomerase Inhibitor Effective in Cells Overexpressing Drug Efflux Transporters

BACKGROUND:Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS:A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS:The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids

Feeding ecology of the scops owl, Otus scops

All of the published studies but one about the diet of the Eurasian scops owl Otus scops, a nocturnal raptor of conservation concern, were carried out during the breeding period, just before or immediately after the chicks fledged. The species is a trans-Saharian migrant with few resident populations in Europe. Orthoptera make up the staple of its diet in summer. In this study, we investigated the diet of scops owls on the island of Pianosa after the breeding period through the analysis of pellets. A total of 327 fragments belonging to at least 14 taxa were identified from 56 pellets collected after the breeding period, between late August and March. By frequency, invertebrates constituted 80.00% of the diet, with Coleoptera being the most represented order (62.35% of the total diet) and Orthoptera poorly represented (8.24%). Vertebrates included two bird species, three small mammals and the Moorish gecko. Although the meal-to-pellet interval for scops owls is unknown, we suggest that the bank vole, which is not recorded on any Italian island, and possibly the wild mice, may have been preyed upon in nearby areas, before a migratory movement towards a warm area (e.g. Pianosa) occurred