Doxorubicin-induced cardiotoxicity: pyridoxamine to the rescue?

Abstract

Cardiovascular disease (CVD) and cancer are responsible for a significant proportion of deaths in our society. Both diseases are linked through shared risk factors and underlying pathophysiological mechanisms, resulting in higher CVD incidence in cancer patients and vice versa. CVDs may also develop after cancer therapy, referred to as cancer treatment-related cardiac dysfunction (CTRCD). This condition frames within the field of cardio-oncology, involved in detecting, preventing, treating, and investigating CVDs after cancer therapy. Anthracyclines are a class of chemotherapeutic agents associated with cardiac injury, whose exposure leads to a condition described as anthracycline-induced cardiotoxicity. Despite extensive research in the past, the pathogenesis of anthracycline-induced cardiotoxicity is incompletely understood, and strategies to provide long-term cardioprotection without compromising anthracycline activity are lacking. This doctoral dissertation focuses on pyridoxamine (PM) as a novel cardioprotective agent in an animal model of anthracycline-induced cardiotoxicity in which rats were treated with doxorubicin (DOX), the prototypical anthracycline drug. PM is cardioprotective in preclinical CVD models. The mechanism of action of PM is multifactorial, involving the inhibition of mechanisms linked to anthracycline-induced cardiotoxicity. We hypothesized that PM attenuates the development of DOX-induced cardiotoxicity in a rat model by interfering with multiple mechanisms underlying the disease process without compromising the antitumor activity of DOX. The research objectives to test this hypothesis include investigating the effect of PM on DOX antitumor activity in vitro, the cardioprotective potential of PM in an in vivo model of DOX-induced cardiotoxicity and the mechanisms involved, and the diagnostic performance of echocardiography in cardiotoxicity evaluation in our studies. We found that co-administration of PM does not reduce the inhibitory effects of DOX on the viability, proliferation, cytotoxicity, and apoptosis of LA7 rat breast cancer cells. We have applied an animal model that recapitulated the clinical picture of anthracycline-induced cardiotoxicity. In this animal model, we proved that concomitant oral PM administration in DOX-treated rats prevents cardiomyocyte death, myocardial transforming growth factor beta (TGF-β)-regulated fibrotic remodeling, macrophage-driven myocardial inflammation, redox and iron regulation disturbances, and mitochondrial damage in left ventricular (LV) tissue. Moreover, we revealed that, in this animal model of anthracycline-induced cardiotoxicity, LV volumetric changes are more pronounced but occur simultaneously with the deterioration of systolic function, four-dimensional (4D)- and motion mode (M-mode) echocardiography show the best agreement in measuring LV systolic function and volumes, and interobserver variability is minimal. We conclude that PM limits DOX-induced cardiotoxicity by multiple mechanisms without affecting the antitumor effect of DOX, which suggests that PM supplementation may represent a promising future cardioprotective strategy for cancer patients exposed to anthracycline chemotherapy.