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.

Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications

“…In the same model, histamine administration was demonstrated to potentiate ionizing radiation and doxorubicin therapies (Martinel Lamas et al, 2015a,b,d).…”

Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

“…Each form of GPx4 plays protective roles within each organelle, and their dysregulation is associated with disease (12,(16)(17)(18)(19)(20)(21). Indeed, LP levels increased and might serve as key mediators of cardiac injuries in DIC (22,23). We thus hypothesized that the dysregulation of ferroptosis and GPx4 under DOX treatment may be involved in LP accumulation and DIC progression.…”

Role of microRNAs in doxorubicin-induced cardiotoxicity: an overview of preclinical models and cancer patients

“…For obvious reasons, it is not possible to study the mechanism governing cardiotoxicity directly in cancer patients; thus, the clinical relevance of anthracycline-induced chronic cardiotoxicity has triggered many investigations based on the use of animal models, such as rats and mice, to shed some light on the several effects of DOX treatment. In vivo studies are important not only in the cardiac field but also, for example, to establish the teratogenic potential of this compound [ 31 ] and its harmful effects on the liver [ 32 ]. However, the prevalent focus of DOX-based preclinical studies is cardiotoxicity.…”