title: The human amniotic fluid stem cell secretome effectively counteracts doxorubicin-induced cardiotoxicity.
abstract: The anthracycline doxorubicin (Dox) is widely used in oncology, but it may cause a cardiomyopathy with bleak prognosis that cannot be effectively prevented. The secretome of human amniotic fluid-derived stem cells (hAFS) has previously been demonstrated to significantly reduce ischemic cardiac damage. Here it is shown that, following hypoxic preconditioning, hAFS conditioned medium (hAFS-CM) antagonizes senescence and apoptosis of cardiomyocytes and cardiac progenitor cells, two major features of Dox cardiotoxicity. Mechanistic studies with mouse neonatal ventricular cardiomyocytes (mNVCM) reveal that hAFS-CM inhibition of Dox-elicited senescence and apoptosis is associated with decreased DNA damage, nuclear translocation of NF-kB, and upregulation of the NF-kB controlled genes, Il6 and Cxcl1, promoting mNVCM survival. Furthermore, hAFS-CM induces expression of the efflux transporter, Abcb1b, and Dox extrusion from mNVCM. The PI3K/Akt signaling cascade, upstream of NF-kB, is potently activated by hAFS-CM and pre-treatment with a PI3K inhibitor abrogates NF-kB accumulation into the nucleus, modulation of Il6, Cxcl1 and Abcb1b, and prevention of Dox-initiated senescence and apoptosis in response to hAFS-CM. These results support the concept that hAFS are a valuable source of cardioprotective factors and lay the foundations for the development of a stem cell-based paracrine treatment of chemotherapy-related cardiotoxicity.
authors.affiliation: Cardiovascular Biology Laboratory, Department of Internal Medicine, University of Genova and IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Lazzarini
authors.affiliation: Regenerative Medicine Laboratory, Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Balbi
authors.affiliation: Cardiovascular Biology Laboratory, Department of Internal Medicine, University of Genova and IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Altieri
authors.affiliation: Molecular Pathology Unit, IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, IRCCS Centro Cardiologico Monzino, Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gambini
authors.affiliation: Cardiovascular Biology Laboratory, Department of Internal Medicine, University of Genova and IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Canepa
authors.affiliation: Molecular Biology Laboratory, IRCCS Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
authors.affiliation: Molecular Biology Laboratory, IRCCS Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Bosco
authors.affiliation: Human Genetics Laboratory, E.O. Ospedali Galliera, Genova, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coviello
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, IRCCS Centro Cardiologico Monzino, Milano, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pompilio
authors.affiliation: Cardiovascular Biology Laboratory, Department of Internal Medicine, University of Genova and IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brunelli
authors.affiliation: Regenerative Medicine Laboratory, Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Ranieri
authors.initials: R
authors.lastname: Cancedda
authors.affiliation: Cardiovascular Biology Laboratory, Department of Internal Medicine, University of Genova and IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ameri
authors.affiliation: Regenerative Medicine Laboratory, Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Sveva
authors.initials: S
authors.lastname: Bollini
mesh_terms: D000653:Amniotic Fluid / Q000166:cytology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000378:metabolism; D066126:Cardiotoxicity / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects*; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt