title: Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models.
abstract: The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice.
authors.affiliation: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 PB, Buenos Aires, Argentina; Laboratory of Cellular and Molecular Biology, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: D J
authors.initials: DJ
authors.lastname: Martinel Lamas
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET) , Buenos Aires, Argentina.
authors.forename: M B
authors.initials: MB
authors.lastname: Nicoud
authors.affiliation: Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET) , Buenos Aires, Argentina.
authors.forename: H A
authors.initials: HA
authors.lastname: Sterle
authors.affiliation: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 PB , Buenos Aires, Argentina.
authors.forename: E
authors.initials: E
authors.lastname: Carabajal
authors.affiliation: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 PB , Buenos Aires, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Tesan
authors.affiliation: Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires , Buenos Aires, Argentina.
authors.forename: J C
authors.initials: JC
authors.lastname: Perazzo
authors.affiliation: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 PB, Buenos Aires, Argentina; Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: G A
authors.initials: GA
authors.lastname: Cremaschi
authors.affiliation: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 PB , Buenos Aires, Argentina.
authors.forename: E S
authors.initials: ES
authors.lastname: Rivera
authors.affiliation: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 PB, Buenos Aires, Argentina; Laboratory of Cellular and Molecular Biology, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: V A
authors.initials: VA
authors.lastname: Medina