Vicrostatin – An Anti-Invasive Multi-Integrin Targeting Chimeric Disintegrin with Tumor Anti-Angiogenic and Pro-Apoptotic Activities

Similar to other integrin-targeting strategies, disintegrins have previously shown good efficacy in animal cancer models with favorable pharmacological attributes and translational potential. Nonetheless, these polypeptides are notoriously difficult to produce recombinantly due to their particular structure requiring the correct pairing of multiple disulfide bonds for biological activity. Here, we show that a sequence-engineered disintegrin (called vicrostatin or VCN) can be reliably produced in large scale amounts directly in the oxidative cytoplasm of Origami B E. coli. Through multiple integrin ligation (i.e., αvβ3, αvβ5, and α5β1), VCN targets both endothelial and cancer cells significantly inhibiting their motility through a reconstituted basement membrane. Interestingly, in a manner distinct from other integrin ligands but reminiscent of some ECM-derived endogenous anti-angiogenic fragments previously described in the literature, VCN profoundly disrupts the actin cytoskeleton of endothelial cells (EC) inducing a rapid disassembly of stress fibers and actin reorganization, ultimately interfering with EC's ability to invade and form tubes (tubulogenesis). Moreover, here we show for the first time that the addition of a disintegrin to tubulogenic EC sandwiched in vitro between two Matrigel layers negatively impacts their survival despite the presence of abundant haptotactic cues. A liposomal formulation of VCN (LVCN) was further evaluated in vivo in two animal cancer models with different growth characteristics. Our data demonstrate that LVCN is well tolerated while exerting a significant delay in tumor growth and an increase in the survival of treated animals. These results can be partially explained by potent tumor anti-angiogenic and pro-apoptotic effects induced by LVCN

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics

W jaki sposób użytki zielone w okresie opadów mogą modyfikować bilans wodny w warunkach suszy

Taking into account the well-established influence of hillslopes grasslands on runoff processes, the purpose of this study was to investigate how grasslands can affect the water flow pathways on hillslopes, in drought conditions. This study was performed in experimental grassland at plot-scale (e.g., Festuca pratensis), in temperate humid continental climatic conditions of Curvature Subcarpathians, Romania. The rainfall, evapotranspiration, and soil moisture daily data, respectively 208 rainfall and 16 rainfall-runoff events data measured in grassland hills during the growing season (1 April up to 30 September 2015 and 2016) were used. Our results suggest that a runoff event response in extreme drought conditions occurs on grasslands only if precipitation exceeds the threshold of 31 mm Hortonian overland flow (HOF), while this threshold drops to 17 mm during moderate droughts and up to 8 mm for wet conditions. The rainfall events up to 16 mm proved to be insufficient to completely saturate the soil. Therefore, HOF has only a minor contribution in drought conditions, on grassland and light on bare soil. A complementary and negative effect of grasslands in drought conditions is the water resources suppressing on hillslopes.Biorąc pod uwagę dobrze znany wpływ użytków zielonych na stokach na odpływ wody, celem było zbadanie, jak te siedliska mogą wpływać na drogi przepływu wody w warunkach suszy. Badania prowadzono na eksperymentalnych poletkach porośniętych na przykład przez Festuca pratensis w warunkach umiarkowanie wilgotnego klimatu kontynentalnego na Pogórzu Karpackim w Rumunii. Do analizy użyto dane o opadach, ewapotranspiracji i wilgotności gleby (208 danych o opadach i 16 kombinacji opad–odpływ) pozyskanych z pomiarów na pagórkach pokrytych roślinnością trawiastą w sezonie wegetacyjnym od 1 kwietnia do 30 września w latach 2015 i 2016. Uzyskane wyniki wskazują, że odpływ w warunkach skrajnej suszy występuje w siedliskach trawiastych jedynie wtedy, gdy opad przekroczy wartość 31 mm powierzchniowego odpływu Hortona (HOF). Wartość HOF maleje do 17 mm w warunkach umiarkowanej suszy i do 8 mm w warunkach wilgotnych. Okresy opadów do 16 mm okazały się niewystarczające do całkowitego nasycenia gleby. Z tego powodu przepływ powierzchniowy ma w warunkach suszy znikome znaczenie w siedliskach trawiastych i niewielkie na odkrytej glebie. Komplementarnym i ujemnym skutkiem występowania użytków zielonych jest ograniczenie zasobów wodnych na stokach