PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors.

Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110γ/δ inhibition.

Therapeutic targeting of Polo-like kinase-1 and Aurora kinases in T-cell acute lymphoblastic leukemia.

Polo-like kinases (PLKs) and Aurora kinases (AKs) act as key cell cycle regulators in healthy human cells. In cancer, these protein kinases are often overexpressed and dysregulated, thus contributing to uncontrolled cell proliferation and growth. T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy arising in the thymus from T-cell progenitors.

Targeting phosphatidylinositol 3-kinase signaling in acute myelogenous leukemia.

Introduction: Despite continuous advances in our knowledge of the biology of acute myelogenous leukemia (AML), the prognosis of AML patients treated with standard chemotherapy is still poor, especially in the elderly. Therefore, there is a need for novel targeted and less toxic therapies, particularly for patients who develop resistance to traditional chemotherapeutic drugs. Constitutively active phosphatidylinositol 3-kinase (PI3K) signaling characterizes many types of tumors, including AML, where it negatively influences response to therapeutic treatments.

Downregulation of HuR as a new mechanism of doxorubicin resistance in breast cancer cells.

Background: HuR, an RNA binding protein involved in the post-transcriptional regulation of a wide spectrum of mRNAs, has been demonstrated to be a determinant of carcinogenesis and tumor aggressiveness in several cancer types. In this study, we investigated the role of HuR in the apoptosis and in the chemoresistance induced by the widely used anticancer drug doxorubicin in human breast cancer cells (MCF-7).

Results: We showed that HuR acts in the early phase of cell response to doxorubicin, being induced to translocate into the cytoplasm upon phosphorylation.

Eosinophil as a cellular target of the ocular anti-allergic action of mapracorat, a novel selective glucocorticoid receptor agonist.

Purpose: Glucocorticoids can either suppress gene transcription (transrepression) or activate it (transactivation). This latter process may contribute to certain side effects caused by these agents. Mapracorat (also known as BOL-303242-X or ZK 245186) is a novel selective glucocorticoid receptor agonist that maintains a beneficial anti-inflammatory activity but seems to be less effective in transactivation, resulting in a lower potential for side effects; it has been proposed for the topical treatment of inflammatory skin disorders.

Effect of ΔFosB overexpression on opioid and cannabinoid receptor-mediated signaling in the nucleus accumbens.

The stable transcription factor ΔFosB is induced in the nucleus accumbens (NAc) by chronic exposure to several drugs of abuse, and transgenic expression of ΔFosB in the striatum enhances the rewarding properties of morphine and cocaine. However, the mechanistic basis for these observations is incompletely understood. We used a bitransgenic mouse model with inducible expression of ΔFosB in dopamine D(1) receptor/dynorphin-containing striatal neurons to determine the effect of ΔFosB expression on opioid and cannabinoid receptor signaling in the NAc.

beta-Arrestin 2-mediated heterologous desensitization of IGF-IR by prolonged exposure of SH-SY5Y neuroblastoma cells to a mu opioid agonist.

Prolonged (12h) exposure of SH-SY5Y neuroblastoma cells to the mu-opioid receptor (MOPr) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) causes homologous desensitization as well as heterologous desensitization of the extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation induced by insulin-like growth factor (IGF)-I. Brief (15 min) but not prolonged exposure to DAMGO transregulates the insulin-like growth factor-I (IGF-I) receptor, as evidenced by its phosphorylation in the absence of IGF-I. Silencing of beta-arrestin 2 uncouples the crosstalk between the two receptors, thus maintaining IGF-I-mediated receptor phosphorylation and ERK 1/2 activation even after prolonged DAMGO exposure.

Synthesis and conformational analysis of cyclotetrapeptide mimetic beta-turn templates and validation as 3D scaffolds.

The conformations of all stereoisomers of PMRI cyclotetrapeptide mimetics 1-8 are essentially determined by the predisposition of the diamine to stabilize beta-turns. The peptide mimetics can be regarded as 3D scaffolds for designing molecules with a predictable display of the pharmacophores. We used the models for testing novel RGD analogues as alpha(v)beta(3)-integrin receptor antagonists.

New coumarin-based anti-inflammatory drug: putative antagonist of the integrins alphaLbeta2 and alphaMbeta2.

This study was conducted to investigate putative antagonism of integrin receptors alphaMbeta2 and alphaLbeta2 by a novel coumarin derivative (BOL-303225-A), its efficacy in-vivo after retinal ischaemia-reperfusion injury, and its bioavailability in rat plasma. A cellular adhesion assay in Jurkat and U937 cells, and a flow cytometry assay with an antibody against the beta2 subunit were conducted. BOL-303225-A bioavailability in rat plasma and the retinal levels of myeloperoxidase (MPO) after ischaemia-reperfusion injury were evaluated after oral administration (10 mg kg(-1)).

Contribution of alpha4beta1 integrin to the antiallergic effect of levocabastine.

Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist. In allergic conjunctivitis (AC), it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC.

Synthesis and biological evaluation of non-peptide alpha(v)beta(3)/alpha(5)beta(1) integrin dual antagonists containing 5,6-dihydropyridin-2-one scaffolds.

Small constrained non-peptidic molecules consisting of a polyfunctionalized rigid core, carrying appendages corresponding to arginine and aspartic acid side chains, have been recently reported to be promising for drug development. In this work, the 5,6-dihydropyridin-2-one was envisaged as a scaffold to turn into potential integrin ligands, introducing a carboxylic acid and a basic appendage. The synthesis and the antiadhesion activity of a small library of peptidomimetics capable to recognize alpha(v)beta(3) and alpha(5)beta(1) integrins has been herein reported.

Inhibition of cancer cell adhesion by heterochiral Pro-containing RGD mimetics.

In this paper, we describe the synthesis of a selected library of heterochiral d-Pro-containing RGD-peptidomimetics (RpD) and we investigate the biological activity as inhibitors of fibronectin adhesion to SK-MEL-24 tumor cells. In particular, peptides 4 and 8 showed an IC(50) in the 10(-8)M range. Despite the linear structure, the peptides tend to adopt a folded conformation in a polar environment.