title: Delivery of doxorubicin across the blood-brain barrier by ondansetron pretreatment: a study in vitro and in vivo.
abstract: Doxorubicin (Dox) has got a limited efficacy in the treatment of central nervous system tumors because of its poor penetration through blood-brain barrier mediated by MDR efflux transporters. We investigated the possibility that ondansetron (Ond) enhances Dox cytotoxicity in cell lines interfering with P-glycoprotein and increases Dox concentration in rat brain tissues. The MDR phenotype was studied using human hepatocellular carcinoma cell line PLC/PRF/5 (P5 and P1(0.5) clones), two subclones of NIH 3T3 cells (PSI-2 and PN1A) and two glioblastoma cell lines (A172, U87MG). Rats were pretreated with Ond before injection of Dox. Quantitative analysis of Dox was performed by mass spectrometry. Our in vitro experiments demonstrated that Ond at 10 µg/ml is not toxic to all cell lines. However, Ond reverses the MDR phenotype in P1(0.5) and PN1A cell lines. In addition, we showed that pretreatment with Ond increases Dox concentration in rat brain tissues, without increasing acute heart and renal toxicity.
authors: Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy; Department of Health Sciences, University of Florence, Florence, Italy. Electronic address: i.sardi@meyer.it.
authors: Iacopo
authors: I
authors: Sardi
authors: Second Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence University, Florence, Italy.
authors: Ornella
authors: O
authors: Fantappiè
authors: Newborn Screening, Biochemistry and Pharmacology Laboratory, Paediatric Neurology Unit and Laboratories, Department of Neuroscience, Meyer Children's Hospital, Florence, Italy.
authors: Giancarlo
authors: G
authors: la Marca
authors: Department of Health Sciences, Section of Pharmacology and Clinical Oncology, University of Florence, Florence, Italy.
authors: Maria Grazia
authors: MG
authors: Giovannini
authors: Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy; Department of Health Sciences, University of Florence, Florence, Italy.
authors: Anna Lisa
authors: AL
authors: Iorio
authors: Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy; Department of Health Sciences, University of Florence, Florence, Italy.
authors: Martina
authors: M
authors: da Ros
authors: Newborn Screening, Biochemistry and Pharmacology Laboratory, Paediatric Neurology Unit and Laboratories, Department of Neuroscience, Meyer Children's Hospital, Florence, Italy.
authors: Sabrina
authors: S
authors: Malvagia
authors: Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy; Department of Health Sciences, University of Florence, Florence, Italy.
authors: Stefania
authors: S
authors: Cardellicchio
authors: Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy; Department of Health Sciences, University of Florence, Florence, Italy.
authors: Laura
authors: L
authors: Giunti
authors: Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy; Department of Health Sciences, University of Florence, Florence, Italy.
authors: Maurizio
authors: M
authors: de Martino
authors: Second Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence University, Florence, Italy.
authors: Roberto
authors: R
authors: Mazzanti
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D017294:Ondansetron / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D017294:Ondansetron; D004317:Doxorubicin
keywords: Blood–brain barrier; Brain tumors; Doxorubicin; Multidrug resistance; Ondansetron