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1.
Life Sci Alliance ; 7(1)2024 01.
Article in English | MEDLINE | ID: mdl-37923359

ABSTRACT

The hERG1 potassium channel is aberrantly over expressed in tumors and regulates the cancer cell response to integrin-dependent adhesion. We unravel a novel signaling pathway by which integrin engagement by the ECM protein fibronectin promotes hERG1 translocation to the plasma membrane and its association with ß1 integrins, by activating girdin-dependent Gαi3 proteins and protein kinase B (Akt). By sequestering hERG1, ß1 integrins make it avoid Rab5-mediated endocytosis, where unbound channels are degraded. The cycle of hERG1 expression determines the resting potential (Vrest) oscillations and drives the cortical f-actin dynamics and thus cell motility. To interpret the slow biphasic kinetics of hERG1/ß1 integrin interplay, we developed a mathematical model based on a generic balanced inactivation-like module. Integrin-mediated cell adhesion triggers two contrary responses: a rapid stimulation of hERG1/ß1 complex formation, followed by a slow inhibition which restores the initial condition. The protracted hERG1/ß1 integrin cycle determines the slow time course and cyclic behavior of cell migration in cancer cells.


Subject(s)
Integrins , Neoplasms , Humans , Ether-A-Go-Go Potassium Channels/genetics , Ether-A-Go-Go Potassium Channels/metabolism , Integrin beta1/metabolism , Integrins/metabolism , Neoplasms/pathology , Signal Transduction
2.
Cancers (Basel) ; 15(7)2023 Mar 28.
Article in English | MEDLINE | ID: mdl-37046674

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) represents an unmet medical need. Difficult/late diagnosis as well as the poor efficacy and high toxicity of chemotherapeutic drugs result in dismal prognosis. With the aim of improving the treatment outcome of PDAC, we tested the effect of combining Gemcitabine with a novel single chain bispecific antibody (scDb) targeting the cancer-specific hERG1/ß1 integrin complex. First, using the scDb (scDb-hERG1-ß1) in immunohistochemistry (IHC), Western blot (WB) analysis and immunofluorescence (IF), we confirmed the presence of the hERG1/ß1 integrin complex in primary PDAC samples and PDAC cell lines. Combining Gemcitabine with scDb-hERG1-ß1 improved its cytotoxicity on all PDAC cells tested in vitro. We also tested the combination treatment in vivo, using an orthotopic xenograft mouse model involving ultrasound-guided injection of PDAC cells. We first demonstrated good penetration of the scDb-hERG1-ß1 conjugated with indocyanine green (ICG) into tumour masses by photoacoustic (PA) imaging. Next, we tested the effects of the combination at either therapeutic or sub-optimal doses of Gemcitabine (25 or 5 mg/kg, respectively). The combination of scDb-hERG1-ß1 and sub-optimal doses of Gemcitabine reduced the tumour masses to the same extent as the therapeutic doses of Gemcitabine administrated alone; yielded increased survival; and was accompanied by minimised side effects (toxicity). These data pave the way for a novel therapeutic approach to PDAC, based on the combination of low doses of a chemotherapeutic drug (to minimize adverse side effects and the onset of resistance) and the novel scDb-hERG1-ß1 targeting the hERG1/ß1 integrin complex as neoantigen.

3.
J Inorg Biochem ; 204: 110933, 2020 03.
Article in English | MEDLINE | ID: mdl-31825796

ABSTRACT

We report the synthesis and biological evaluation of a ternary copper complex, [Cu(5HTP)(phen)(H2O)](NO3).2H2O, with the antioxidant agent 5-hydroxytryptophan (5-HTP) and phenanthroline (phen, added to improve its lipophilicity and membrane transport). The crystal structure of the complex was determined by X-ray diffraction methods. The complex showed antioxidant, antimicrobial, antitumor and antimetastatic properties with an adequate safety profile. The interaction of the metal with phen promotes cellular copper accumulation and cytotoxicity on human lung A549 cell line (IC50 = 3.6 µM). Furthermore, the viability of the normal human fetal lung fibroblast cell line (MRC-5) is not altered by the complex. An oxidative stress mechanism for the anticancer effect has been determined: cellular increase of reactive oxygen species (ROS), decrease of the glutathione (GSH) and oxidized GSH (GSSG) ratio and alteration of the mitochondrial potential. The complex also displays antimetastatic activities with inhibition of cell adhesion, invasion and migration. It has not mutagenic behavior and no toxicity on Artemia salina indicating its potential to act as an effective and safety antimicrobial and antitumor drug.


Subject(s)
5-Hydroxytryptophan/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Copper/chemistry , Lung Neoplasms/drug therapy , Phenanthrolines/chemistry , A549 Cells , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Apoptosis/drug effects , Artemia/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Copper/pharmacology , Humans , Phenanthrolines/pharmacology , Toxicity Tests
4.
Mol Biol Rep ; 46(1): 867-885, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30506507

ABSTRACT

Copper complexes with transformed methimazole ligand have been synthesized and characterized by elemental analysis, conductivity measurements, thermogravimetric analysis, EPR, FTIR and UV-Vis spectroscopies. Results support their stoichiometries and geometrical structures: [Cu(C4H5N2S)2Cl2]·2H2O(1), [Cu(C8H10N4S)SO4H2O](2) and [Cu(C8H10N4S)SO4](3). ((C4H5N2)2S: bis(l-methylimidazol-2-yl)sulfide; (C4H5N2S)2 = Bis[bis(l-methylimidazol-2-yl)disulfide]) Concurrently, the structurally distinct soluble species corresponding to complexes (1) and (2) were subsequently used in an in vitro investigation of their potential biological properties. In view of their possible pharmaceutical activity, the complexes were in vitro evaluated as phosphatase acid inhibitors. Their radical bio-protective effects were also studied measuring the effect against DPPH• and O2•- radicals. Additional catalytic properties as peroxidase mimics were evaluated using Michaelis-Menten kinetic model by means of phenol red and pyrogallol assays. The complexes exhibited catalytic bromination activity and the ability to oxidize pyrogallol substrate indicating that they can be considered as functional models. The relationships between the structures and the in vitro biological activities have also been considered. Serum protein albumin has attracted the greatest interest as drug carrier and the affinity of biological/pharmaceutical compound is relevant to the development of new medicine. In that sense, interaction studies by fluorescence and EPR spectroscopies were performed showing the binding capacity of the complexes.


Subject(s)
Acid Phosphatase/antagonists & inhibitors , Copper/pharmacology , Osteoporosis/drug therapy , Peroxidases/metabolism , Protective Agents/therapeutic use , Superoxide Dismutase/metabolism , Acid Phosphatase/metabolism , Animals , Binding Sites , Biphenyl Compounds/chemistry , Catalysis , Cattle , Electron Spin Resonance Spectroscopy , Kinetics , Oxidation-Reduction , Picrates/chemistry , Protective Agents/pharmacology , Reactive Oxygen Species/metabolism , Serum Albumin, Bovine/metabolism , Spectrometry, Fluorescence , Thermodynamics , Time Factors
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