Evaluation of the cytoprotective action of nebivolol on cyclophosphamide-induced cardiac damage.

• Grant number: 22/14492-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): February 01, 2023
• Effective date (End): November 30, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Barbara Michelli Marchetti
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Nitrogen mustards were the first drugs used to treat cancer. Cyclophosphamide is a nitrogen mustard widely used (alone or in combination) in the treatment of neuroblastoma, myeloma, lymphoma and also in ovarian, lung or breast cancer. One factor that limits the use of cyclophosphamide is its toxic effect that affects distinctive organs and tissues including lung, bladder, bone marrow, thymus, spleen, kidneys and heart. Cyclophosphamide-induced cardiotoxicity is directly related to the drug dose and occurs in 20 to 25% of patients that are treated with the drug. The molecular mechanism by which cyclophosphamide induces its cardiotoxic effect is complex and involves the activation of different cellular pathways. In general, there is an increase in the production of reactive oxygen species (ROS), lipid peroxidation, accumulation of intracellular calcium, induction of apoptosis and an increase in the synthesis of pro-inflammatory proteins. However, it is important to highlight that the increase in oxidative stress with consequent production of ROS is a central mechanism of this response, since it is considered the initial response that triggers the activation of cellular pathways that will mediate pro-inflammatory and apoptosis responses. In this scenario, the enzyme nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase plays an important role in mediating the harmful effects of cyclophosphamide on the heart, since it acts as the main source for the generation of ROS.The use of cytoprotective compounds can increase survival and improve the quality of life of patients using cyclophosphamide, as it allows increasing therapeutic doses of antitumor drugs without compromising their pharmacological action. Thus, the evaluation of the cytoprotective action of different compounds is of paramount interest. Drugs with antioxidant action have been tested as cytoprotective agents against the toxic effects of cyclophosphamide in different organs including bladder and lung. Nebivolol is a third-generation ²-blocker that, in addition to acting as a selective antagonist of ²1-adrenergic receptors, promotes additional effects that include activation of ²3-adrenergic receptors, antagonism of ±1-adrenergic receptors and antioxidant effect. The antioxidant effects of nebivolol have been described in different tissues including the heart where the drug reduced the expression of the enzyme NAD(P)H oxidase, responsible for the production of ROS. Considering that oxidative stress is a central element of cyclophosphamide-induced cardiac toxicity and that nebivolol has an antioxidant action in this tissue, the hypothesis of the present study is that nebivolol will prevent cardiac damage caused by cyclophosphamide by a mechanism that involves reduction of the oxidative stress induced by this chemotherapy. Thus, the present study was designed to assess whether nebivolol will prevent cardiac damage caused by cyclophosphamide and the mechanisms involved in this response.