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Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis
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نویسنده
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Andreucci Elena ,Peppicelli Silvia ,Carta Fabrizio ,Brisotto Giulia ,Biscontin Eva ,Ruzzolini Jessica ,Bianchini Francesca ,Biagioni Alessio ,Supuran Claudiu T. ,Calorini Lido
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منبع
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journal of molecular medicine - 2017 - دوره : 95 - شماره : 12 - صفحه:1341 -1353
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چکیده
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Among the players of the adaptive response of cancer cells able to promote a resistant and aggressive phenotype, carbonic anhydrase ix (caix) recently has emerged as one of the most relevant drug targets. indeed, caix targeting has received a lot of interest, and selective inhibitors are currently under clinical trials. hypoxia has been identified as the master inductor of caix, but, to date, very few is known about the influence that another important characteristic of tumor microenvironment, i.e., extracellular acidosis, exerts on caix expression and activity. in the last decades, acidic microenvironment has been associated with aggressive tumor phenotype endowed with epithelial-to-mesenchymal transition (emt) profile, high invasive and migratory ability, apoptosis, and drug resistance. we demonstrated that melanoma, breast, and colorectal cancer cells transiently and chronically exposed to acidified medium (ph 6.7 ± 0.1) showed a significantly increased caix expression compared to those grown in standard conditions (ph 7.4 ± 0.1). moreover, we observed that the caix inhibitor fc16-670a (also named slc-0111, which just successfully ended phase i clinical trials) not only prevents such increased expression under acidosis but also promotes apoptotic and necrotic programs only in acidified cancer cells. thus, caix could represent a selective target of acidic cancer cells and fc16-670a inhibitor as a useful tool to affect this aggressive subpopulation characterized by conventional therapy escape.
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کلیدواژه
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Acidosis of tumor microenvironment ,Carbonic anhydrase IX (CAIX) ,FC16-670A CAIX inhibitor ,Apoptosis
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آدرس
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University of Florence, Italy. Istituto Toscano Tumori (ITT), Italy, University of Florence, Italy. Istituto Toscano Tumori (ITT), Italy, University of Florence, Department of NEUROFARBA, Italy, University of Padova, Italy. Immunology and Molecular Oncology Unit, IOV-IRCCS, Italy. C.R.O. National Cancer Institute, Traslational Research Department, Italy, C.R.O. National Cancer Institute, Traslational Research Department, Italy, University of Florence, Italy, University of Florence, Italy. Istituto Toscano Tumori (ITT), Italy, University of Florence, Department of Surgery and Translational Medicine, Italy, University of Florence, Department of NEUROFARBA, Italy, University of Florence, Italy. Istituto Toscano Tumori (ITT), Italy. Excellence Centre for Research, Italy
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Authors
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