title: Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling.
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.
authors.affiliation: Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Brandolini
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Cristiano
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fidoamore
authors.affiliation: Dompé Farmaceutici SpA, Via Santa Lucia, Milano, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: De Pizzol
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Di Giacomo
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.|National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy.
authors.forename: Tiziana Marilena
authors.initials: TM
authors.lastname: Florio
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Confalone
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.|National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Galante
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Cinque
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Benedetti
authors.affiliation: Dompé Farmaceutici SpA, Via Santa Lucia, Milano, Italy.
authors.forename: Pier Adelchi
authors.initials: PA
authors.lastname: Ruffini
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cifone
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.|National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Alecci
authors.affiliation: Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Allegretti
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.|National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Cimini
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D023062:Receptors, Interleukin-8A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D023062:Receptors, Interleukin-8A; D013449:Sulfonamides; D017239:Paclitaxel; C490707:reparixin
keywords: preclinical MRI