The Development of Peptide-Based Tools for the Analysis of Angiogenesis

SummaryLimitations to the application of molecularly targeted cancer therapies are the inability to accurately match patient with effective treatment and the absence of a prompt readout of posttreatment response. Noninvasive agents that rapidly report vascular endothelial growth factor (VEGF) levels using positron emission tomography (PET) have the potential to enhance anti-angiogenesis therapies. Using phage display, two distinct classes of peptides were identified that bind to VEGF with nanomolar affinity and high selectivity. Co-crystal structures of these different peptide classes demonstrate that both bind to the receptor-binding region of VEGF. 18F-radiolabelling of these peptides facilitated the acquisition of PET images of tumor VEGF levels in a HM7 xenograph model. The images obtained from one 59-residue probe, 18F-Z-3B, 2 hr postinjection are comparable to those obtained with anti-VEGF antibody B20 72 hr postinjection. Furthermore, VEGF levels in growing SKOV3 tumors were followed using 18F-Z-3B as a PET probe with VEGF levels increasing with tumor size

Glyburide inhibits the Cryopyrin/Nalp3 inflammasome

Glyburide, a sulfonylurea drug commonly used to treat type 2 diabetes, shuts down IL-1β secretion by preventing Cyropyrin activation

A Negative Activation Energy For Luminescence Decay: Specific Solvation Effects On The Emission Properties Of Bis(2,2\u27-bipyridine)(3,5-dicarboxy-2,2\u27-bipyridine)ruthenium(ii) Chloride

A new mixed-ligand polypyridylruthenium(II) complex, [Ru(bpy)(2)L]Cl-2, has been prepared where bpy = 2,2\u27-bipyridine and L = 3,5-dicarboxy-2,2\u27-bipyridine. The ligand L is a non-symmetrically-substituted 2,2\u27-bipyridine having two hydrophilic carboxylate groups located at the 3- and 5-positions of only one of its two pyridyl rings. In acetonitrile, the photophysical properties of the metal complex include a long-lived excited state (lambda(em) = 637 nm, tau = 846 +/- 11 ns, phi = 0.046 at 295 K) whose decay involves an activated crossing to higher energy ligand field states (E(a) = 4170 +/- 200 cm(-1)). This behavior is similar to that observed for other ruthenium tris(bipyridyl) compounds. In contrast, the title compound displays several unusual photophysical properties in aqueous solution. These include a strongly red-shifted emission (lambda(em) = 685 nm) having a short, pH-dependent lifetime which is quenched by an excited-state proton transfer from solvent. The completely deprotonated form of the molecule is the dominant emissive species. Surprisingly, under neutral conditions the excited-state lifetime increases with increasing temperature, from a value of tau = 54 +/- 1 ns (lambda(em) = 686 nm, phi(em) = 0.0036) at 280 K to tau = 75 +/- 1 ns (lambda(em) = 675 nm, phi(em) = 0.0053) at 360 K. The data are fit to the Arrhenius expression to give E(a) = -270 +/- 15 cm(-1) in H2O and E(a) = -178 +/- 10 Thermochromic emission data and temperature-induced energy gap law behavior indicate that the unique photophysical properties of this compound are due to specific interactions involving protic solvent

Requirement of Nuclear Factor κB for Smac Mimetic-Mediated Sensitization of Pancreatic Carcinoma Cells for Gemcitabine-Induced Apoptosis12

Defects in apoptosis contribute to treatment resistance and poor outcome of pancreatic cancer, calling for novel therapeutic strategies. Here, we provide the first evidence that nuclear factor (NF) κB is required for Smac mimetic-mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. The Smac mimetic BV6 cooperates with gemcitabine to reduce cell viability and to induce apoptosis. In addition, BV6 significantly enhances the cytotoxicity of several anticancer drugs against pancreatic carcinoma cells, including doxorubicin, cisplatin, and 5-fluorouracil. Molecular studies reveal that BV6 stimulates NF-κB activation, which is further increased in the presence of gemcitabine. Importantly, inhibition of NF-κB by overexpression of the dominant-negative IκBα superrepressor significantly decreases BV6- and gemcitabine-induced apoptosis, demonstrating that NF-κB exerts a proapoptotic function in this model of apoptosis. In support of this notion, inhibition of tumor necrosis factor α (TNFα) by the TNFα blocking antibody Enbrel reduces BV6- and gemcitabine-induced activation of caspase 8 and 3, loss of mitochondrial membrane potential, and apoptosis. By demonstrating that BV6 and gemcitabine trigger a NF-κB-dependent, TNFα-mediated loop to activate apoptosis signaling pathways and caspase-dependent apoptotic cell death, our findings have important implications for the development of Smac mimetic-based combination protocols in the treatment of pancreatic cancer