Mechanisms and management of doxorubicin cardiotoxicity

Abstract

Doxorubicin is an effective anti-tumor agent with a cumulative dose-dependent cardiotoxicity. In addition to its principal toxic mechanisms involving iron and redox reactions, recent studies have described new mechanisms of doxorubicin-induced cell death, including abnormal protein processing, hyper-activated innate immune responses, inhibition of neuregulin-1 (NRG1)/ErbB(HER) signalling, impaired progenitor cell renewal/cardiac repair, and decreased vasculogenesis. Although multiple mechanisms involved in doxorubicin cardiotoxicity have been studied, there is presently no clinically proven treatment established for doxorubicin cardiomyopathy. Iron chelator dexrazoxane, angiotensin converting enzyme (ACE) inhibitors, and β-blockade have been proposed as potential preventive strategies for doxorubicin cardiotoxicity. Novel approaches such as anti-miR-146 or recombinant NRG1 to increase cardiomyocyte resistance to toxicity may be of interest in the future.

Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II

“…ADR lead to activate proapoptotic signaling pathways through p53 activation (Monti et al 2013). Furthermore, ADR was reported to impair progenitor cell renewal/cardiac repair as well (Shi et al 2011). The cardiomyocytes have a limited regenerative capacity which may be an explanation for cumulative toxicity of ADR on cardiac cell due to progressive loss.…”

Myocardial Self-Repair and Congenital Heart Disease

“…Given the genetic nature of known lesions in sarcomeric proteins in this disease (Frazier et al, 2011), one may anticipate that the progenitor cell population may also harbor the same mutant alleles and therefore the expansion of that population may provide no benefit. However, for cardiomyopathy induced by chemical injury such as doxorubicin/adriamycin therapy (Shi et al, 2011), strategies to promote expansion of the resident CPC population could be considered an adjuvant or co-therapy used to mitigate cardiotoxicity. It is important to consider that, although the resident CPC may have an advantage in already being present within the muscular wall of the heart, therapies designed to help recruit bone marrowderived CPC (and EPC) (see section 3.…”

Aggressive chemotherapy in frail patients with diffuse large B-cell lymphoma: The role of pegylated liposomal doxorubicin

“…The introduction of liposomal and pegylated liposomal anthracyclines open a new options in treatment of this setting of patients because these drugs showed similar antitumoral activity and reduced cardiac toxicity [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] .…”