title: Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells.
abstract: Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control, and that this activity is likely due to effects on both BC and microenvironment cells.
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Talarico
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Orecchioni
authors.affiliation: Research and Statistics Department, IRCCS "Tecnologie Avanzate e Modelli Assistenziali in Oncologia" Arcispedale S. Maria Nuova, Reggio Emilia, Italy.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Dallaglio
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Reggiani
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancuso
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Calleri
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Gregato
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Labanca
authors.affiliation: Research and Statistics Department, IRCCS "Tecnologie Avanzate e Modelli Assistenziali in Oncologia" Arcispedale S. Maria Nuova, Reggio Emilia, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rossi
authors.affiliation: Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy.|Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Noonan
authors.affiliation: Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Albini
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology*; D001262:Atenolol / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D009243:NAD / Q000378:metabolism; D009362:Neoplasm Metastasis; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009243:NAD; D001262:Atenolol; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D042967:Electron Transport Complex I; D001241:Aspirin