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Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Doxorubicin and histamine effects on TBARS levels of H4R−/− mice compared with WT Balb/c mice. TBARS levels were determined in mice (a) heart and (b) liver of WT and KO mice. Data are expressed as nmol/mg of tissue. (8–12 mice per group, *P<0.05 versus WT Control; #P<0.05, ##P<0.01 versus WT Dox).
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fig4: Doxorubicin and histamine effects on TBARS levels of H4R−/− mice compared with WT Balb/c mice. TBARS levels were determined in mice (a) heart and (b) liver of WT and KO mice. Data are expressed as nmol/mg of tissue. (8–12 mice per group, *P<0.05 versus WT Control; #P<0.05, ##P<0.01 versus WT Dox).

Mentions: Hearts of Dox-treated WT mice exhibited the expected histopathological abnormalities, including focal necrosis and vascular damage that were accompanied by a significant increase in cardiac lipid peroxidation compared with saline-treated control mice (Figures 1C and 4a). Histamine markedly reduced histopathological changes, preserving muscle bands and vasculature and also blunted the Dox-induced rise in TBARS levels (Figures 1C and 4a).


Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models
Doxorubicin and histamine effects on TBARS levels of H4R−/− mice compared with WT Balb/c mice. TBARS levels were determined in mice (a) heart and (b) liver of WT and KO mice. Data are expressed as nmol/mg of tissue. (8–12 mice per group, *P<0.05 versus WT Control; #P<0.05, ##P<0.01 versus WT Dox).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979467&req=5

fig4: Doxorubicin and histamine effects on TBARS levels of H4R−/− mice compared with WT Balb/c mice. TBARS levels were determined in mice (a) heart and (b) liver of WT and KO mice. Data are expressed as nmol/mg of tissue. (8–12 mice per group, *P<0.05 versus WT Control; #P<0.05, ##P<0.01 versus WT Dox).
Mentions: Hearts of Dox-treated WT mice exhibited the expected histopathological abnormalities, including focal necrosis and vascular damage that were accompanied by a significant increase in cardiac lipid peroxidation compared with saline-treated control mice (Figures 1C and 4a). Histamine markedly reduced histopathological changes, preserving muscle bands and vasculature and also blunted the Dox-induced rise in TBARS levels (Figures 1C and 4a).

View Article: PubMed Central - PubMed

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&thinsp;mg/kg for rats and 1&thinsp;mg/kg for mice, daily subcutaneous injection starting 24&thinsp;h before treatment with Dox), Dox (2&thinsp;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.

No MeSH data available.