Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling

// Laura Brandolini 1, * , Loredana Cristiano 2, * , Alessia Fidoamore 2 , Maria De Pizzol 3 , Erica Di Giacomo 2 , Tiziana Marilena Florio 2, 4 , Giuseppina Confalone 2 , Angelo Galante 2, 4 , Benedetta Cinque 2 , Elisabetta Benedetti 2 , Pier Adelchi Ruffini 3 , Maria Grazia Cifone 2 , Antonio Giordano 5, 6 , Marcello Alecci 2, 4 , Marcello Allegretti 1 , Annamaria Cimini 2, 4, 6 1 Dompé Farmaceutici SpA, Via Campo di Pile, L’Aquila, Italy 2 Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy 3 Dompé Farmaceutici SpA, Via Santa Lucia, Milano, Italy 4 National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy 5 Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy 6 Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA * These authors have contributed equally to this work Correspondence to: Annamaria Cimini, e-mail: annamaria.cimini@univaq.it Marcello Allegretti, e-mail: marcello.allegretti@dompe.com Keywords: preclinical MRI Received: July 31, 2015         Accepted: October 06, 2015        Published: October 26, 2015 ABSTRACT In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population. The available data indicate that IL-8, expressed by tumour cells and induced by chemotherapeutic treatment, is a key regulator of the survival and self-renewal of the population of CXCR1-expressing CSC. Consequently, this investigation on the mechanism of action of the reparixin/paclitaxel combination, was based on the observation that reparixin treatment contained the formation of metastases in several experimental models. However, specific data on the formation of breast cancer brain metastases, which carry remarkable morbidity and mortality to a substantial proportion of advanced breast cancer patients, have not been generated. The obtained data indicate a beneficial use of the drug combination reparixin and paclitaxel to counteract brain tumour metastasis due to CSC, probably due to the combined effects of the two drugs, the pro-apoptotic action of paclitaxel and the cytostatic and anti-migratory effects of reparixin.