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

Effect of tantalum nitride supporting layer on growth and morphology of carbon nanotubes by thermal chemical vapor deposition

International audienceThe role of tantalum nitride (TaNx) thin films as buffer layers on the control of nucleation and growth of aligned carpet-like carbon nanotubes (CNTs) has been proved. TaNx thin films have been deposited on Si by controlled magnetron sputtering process. Multiwall CNTs have been synthesized at 850 degrees C using an aerosol of ferrocene diluted in toluene. Electron microscopy images show a strong correlation between the growth rate and morphology of the CNTs and the initial composition of the TaNx thin films. Multi-scale investigations reveal that both morphology and structure of the CNTs are determined by the properties of the TaNx films. Raman and X-ray photoelectron spectroscopy, high resolution TEM imaging at the submicrometric and atomic scales have been used to confirm these hypotheses

Abstractions and Partial Order Reductions for Checking Branching Properties of Time Petri Nets

The paper deals with verification of untimed branching time properties of Time Petri Nets. The atomic variant of the geometric region method for preserving properties of CTL and ACTL is improved. Then, it is shown, for the first time, how to apply the partial order reduction method to deal with next-time free branching properties of Time Petri Nets. The above two results are combined offering an efficient method for model checking of ACTL X and CTL X properties of Time Petri Nets