Nuovi Approcci Terapeutici contro il Cancro del Colon

This presentation was given in Augusta (Siracusa, Italy) for the 2004 Paul Harris Fellow Award, Rotary Foundation of Rotary International. The lecture discusses the clinical significance of the GC-C pathway and its potential as a therapeutic target for colon cancer and metastatic tumors. It underscores the importance of the dysregulation of the GC-C pathway in promoting colorectal tumorigenesis and of dietary calcium in the GC-C-mediated chemoprevention. Questa e’ la presentazione per il Premio 2004 Paul Harris Fellow del Rotary International (Augusta, Siracusa, Italia). La dissertazione illustra l’importante significato clinico della via moleculare regulata da GC-C e dai suoi ligandi (guanilina, uroguanilina ed ST) per la prevenzione e cura del cancro del coloretto

Targeting the cGMP Pathway to Treat Colorectal Cancer

This presentation was given in 2009 for the Seminar Series of the Department of Molecular Physiology and Biophysics, Thomas Jefferson University (Philadelphia, PA, USA). It illustrates the role of the calcium-sensing receptor (CaR) and matrix metalloproteinase 9 (MMP-9) as critical downstream mediators of the anticancer GCC pathway in intestine. Questa presentazione e’ stata effettuata per il Seminar Series del Dipartimento di Fisiologia Molecolare e Biofisica dell’Universita’ del Thomas Jefferson (Filadelfia, USA). La presentazione illustra l’importante ruolo del CaR ed MMP-9 come mediatori della soppressione del processo tumorale dell’intestino da parte del recettore GCC

Guanylyl Cyclase C (GC-C) Inhibits Human Colon Carcinoma Cell Growth

This is the presentation given for the 2001 Presidential Trainee Young Investigator Award, American Society for Clinical Pharmacology and Therapeutics. An abstract of the presentation has been published in Clin. Pharmacol. Ther., 69(2):P62, 2001. The presentation illustrates the role of the intestinal GC-C receptor as a negative regulator of cell proliferation and cell cycle kinetics in colorectal cancer. It suggests that paracrine GC-C hormones guanylin/uroguanylin are physiological inducers of the proliferation-to-differentiation transition along the intestinal crypt-villus axis. Importantly, the bacterial enterotoxin ST, a potent exogenous GC-C agonist, is offered as a potential cytostatic agent for the prevention and treatment of colorectal cancer in patients. Questa presentazione e’ stata effettuata in occasione del Premio 2001 Presidential Trainee Young Investigator della Societa’ Americana di Farmacologia e Terapia Clinica. La presentazione suggerisce per la prima volta che il recettore intestinale guanilato ciclasi C (GC-C o GCC) ed i suoi ligandi (guanilina, uroguanilina, ST) sono regolatori citostatici della proliferazione delle cellule intestinali, che possono essere utilizzati per la prevenzione e cura del cancro del coloretto

Tumor Epithelial Cell Matrix Metalloproteinase 9 (MMP-9) is a Prognostic Marker in Colorectal Cancer

Presented at American Association Cancer Research in 2008 Zuzga D.S., Gibbons A.V., Li P., Lubbe W.J., Chervoneva I., Pitari G.M. “Tumor epithelial cell MMP-9 is a prognostic marker in colorectal cancer”. In: American Association for Cancer Research Special Conference, Molecular Diagnostics in Cancer Therapeutic Development: Proceedings; 2008 Sept 22-25; Philadelphia, PA. Abstract A40. Colorectal cancer is the second leading cause of cancer-related mortality indeveloped nations. Mortality from colon cancer largely reflects metastasis, thespread of the disease to distant sites. Early diagnosis of pre-metastatic diseaseand accurate stratification of patients with metastasis is pivotal to decreasemortality rates from colon cancer by effectively administering surgery alone orwith chemotherapy. However, specific pathological markers of colorectal cancermetastasis have not emerged. Matrix metalloproteinase 9 (MMP-9) is a keyregulator of metastasis and a therapeutic target in colon cancer. Here, MMP-9overexpression in pure tumor epithelial, but nor stromal, cell populations frompatients was associated with metastatic colorectal cancer progression as definedby RT-PCR and confirmed by immunostaining. Thus, tumors with increasedMMP-9 expression compared to matched normal adjacent tissues alwaysexhibited metastatic dissemination. In particular, MMP-9 overexpression in tumorepithelial cells, compared to normal epithelial cells, specifically predicted lymphnode involvement. Importantly, patients with relative increase of MMP-9 levels intumor epithelial cells were characterized by more advanced disease stages, withsignificantly higher proportion of regional lymph nodes harboring metastasis,compared to patients with a relative decrease in MMP-9 expression. Together,these observations suggest tumor epithelial cell MMP-9 is a novel prognosticmarker that may be exploited for more efficient disease stage stratification andtherapeutic regimen selection in patients with colorectal cancer

Overexpression of matrix metalloproteinase 9 in tumor epithelial cells correlates with colorectal cancer metastasis.

Colorectal cancer mortality largely reflects metastasis, the spread of the disease to distant organs. Matrix metalloproteinase 9 (MMP-9) is a key regulator of metastasis and a target for anticancer strategies in colon cancer. Here, the overexpression of MMP-9 in pure tumor epithelial, but nor stromal, cell populations was associated with metastatic progression of colorectal cancer, as defined by reverse transcriptase-polymerase chain reaction (qRT-PCR) and confirmed by immunostaining. Thus, cancer cell MMP-9 represents a novel, selective prognostic and predictive factor that may be exploited for more effective disease stage stratification and therapeutic regimen selection in patients with colorectal cancer

Phosphorylation of vasodilator-stimulated phosphoprotein Ser239 suppresses filopodia and invadopodia in colon cancer.

In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) actin-based organelles in human colon cancer cells. Membrane organelle disassembly reflected specific phosphorylation of VASP Ser239, the cGMP/PKG preferred site, and rapid VASP removal from tumor cell protrusions. Importantly, VASP Ser239 phosphorylation inhibited the proteolytic function of invadopodia, reflected by suppression of the cancer cell ability to digest DQ-collagen IV embedded in Matrigel. These results demonstrate a previously unrecognized role for VASP Ser239 phosphorylation, a single intracellular biochemical reaction, as an effective mechanism which opposes tumor cell shape promoting colon cancer invasion and metastasis. Reconstitution of physiological cGMP circuitry through VASP, in turn, represents an attractive targeted approach for patients with colorectal cancer

Il ruolo dell'endotelio nella patogenesi dell'emicrania

Dottorato di ricerca in medicina neurovegetativa. 7. ciclo. A.a. 1995-96. Coordinatore G. Crimi. Tutore A. BianchiConsiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

<i>p</i>-Sulfonato-Calix[4]arene Micelles Stabilize a Povidone Iodine Solution: Supramolecular Interactions, Iodine Retention, and Bactericidal Activity

Povidone iodine (PVPI) is an antiseptic widely used against a broad spectrum of pathogens. However, undesired side-effects are still associated with PVPI treatment due to the irritant effect of iodine. Reducing the concentration of a PVPI formulation could provide safer and more friendly formulations, for routine use and applications in very delicate organs such as the eye. However, managing the storage of a low-concentration solution of PVPI is challenging due to the high iodine volatility. In this study, we demonstrated that an amphiphilic p-sulfonato-calix[4]arene derivative forming micelles (SC4OC6) improves the stability of a 0.1% PVPI aqueous buffered solution. UV-vis and NMR spectra as well as dynamic and electrophoretic light scattering measurements showed that SC4OC6 establishes non-covalent supramolecular interactions with PVPI, resulting in the formation of nanoaggregates with a negatively charged surface. Isothermal titration calorimetry provided the aggregation parameters and evidenced that the formation of the supramolecular assembly is an enthalpically favored process. The interaction of SC4OC6 with PVPI enhances the iodine retention and stability of the solution without affecting the rapid and effective bactericidal activity of PVPI, as demonstrated by a time-killing assay with Staphylococcus epidermidis

Effect of prolonged incubation with copper on endothelium-dependent relaxation in rat isolated aorta

1. We investigated the effects of prolonged exposure to copper (Cu(2+)) on vascular functioning of isolated rat aorta. 2. Aortic rings were exposed to CuSO(4) (3–24 h) in Dulbecco's modified Eagle medium with or without 10% foetal bovine serum (FBS) and then challenged with vasoconstrictors or vasodilators in the absence of Cu(2+). 3. Exposure to 2 μM Cu(2+) in the absence of FBS did not modify the response to phenylephrine (PE) or acetylcholine (ACh) in aortic rings incubated for 24 h. Identical exposure in the presence of FBS increased the contractile response to 1 μM PE by 30% (P<0.05) and impaired the relaxant response to 3 μM ACh or 1 μM A23187 (ACh, from 65.7±7.1 to 6.2±1.1%, n=8; A23187, from 74.6±8.2 to 12.0±0.8%, n=6; P<0.01 for both). Cu(2+) exposure did not affect the relaxant response to NO-donors. 4. Impairment of vasorelaxation appeared 3 h after incubation with 2 μM Cu(2+) and required 12 h to attain a steady state. Vasorelaxation to ACh was partially restored by 1 mM tiron (intracellular scavenger of superoxide ions; maximum relaxation 34.2±6.4%, n=10, P<0.01 vs Cu(2+) alone), whereas catalase, superoxide dismutase or cycloheximide were ineffective. 5. Twenty-four hour-exposure to 2 μM Cu(2+) did not affect endothelium integrity or eNOS expression, and increased the Cu content in arterial rings from 6.8±1.1 to 18.9±2.9 ng mg(−1) wet weight, n=8; P<0.01. 6. Our results show that, in the presence of FBS, prolonged exposure to submicromolar concentrations of Cu(2+) impaired endothelium-dependent vasorelaxation in aortic rings, probably through an intracellular generation of superoxide ions