Doxorubicin-induced cardiotoxicity: causative factors and possible interventions

Abstract

Objectives Doxorubicin (Dox) belongs to the anthracycline drug classification and is a widely administered chemotherapeutic. However, Dox use in therapy is limited by its cardiotoxicity, representing a significant drawback of Dox treatment applicability. A large amount of current research is on reducing Dox-induced cardiotoxicity by developing targeted delivery systems and investigating cardiotoxicity mechanisms. Recently, discrepancies have challenged the traditional understanding of Dox metabolism, mechanisms of action and cardiotoxicity drivers. This review summarises the current knowledge around Dox’s metabolism, mechanisms of anticancer activity, and delivery systems and offers a unique perspective on the relationships between several proposed mechanisms of Dox-induced cardiotoxicity. Key findings While there is a strong understanding of Dox’s pharmacokinetic properties, it is unclear which enzymes contribute to Dox metabolism and how Dox induces its cytotoxic effect in neoplastic and non-neoplastic cells. Evidence suggests that there are several potentially synergistic mechanisms involved in Dox-induced cardiotoxicity. Summary It has become clear that Dox operates in a multifactorial fashion dependent on cellular context. Accumulation of oxidative stress appears to be a common factor in cardiotoxicity mechanisms, highlighting the importance of novel delivery systems and antioxidant therapies.

Seaweed Sargassum aquifolium extract ameliorates cardiotoxicity induced by doxorubicin in rats

“…For instance, DOX might be oxidized to the unstable metabolite “semiquinone,” which is then transformed back to DOX, releasing numerous reactive oxygen species (ROS). ROS triggers different oxidative stress patterns, lipid peroxidation, and membrane and DNA damage (Menna et al 2012 ; Jones and Dass 2022 ). They can also initiate apoptotic cell death pathways (Thorn et al 2011 ; Su et al 2019 ).…”

Mitigation of Cardiovascular Disease and Toxicity through NRF2 Signalling

“…Even at previously perceived low cumulative doses of ≤250 mg/m 2 , the risk of adverse cardiac incidents was increased by 7.8–8.8% [ 158 ] and induced defects in endomyocardial biopsies [ 159 ]. As such, a maximal lifetime exposure has been recommended at 450–500 mg/m 2 [ 160 , 161 ].…”

“…DOX is known to induce oxidative stress, which was believed to be a primary cause of its antitumorigenic activity following measurable increases in ROS from animal and human studies [ 164 ]. However, more recently it has been proposed that ROS formation in itself does not make a large contribution to its on-target mechanism of action due to the relative resistance of many cancer cell types to oxidative stress, as will be discussed later in this review, and the requirement for often supra-clinical DOX doses to induce excessive ROS levels [ 161 , 165 ]. The DOX-induction of ROS may provide a secondary mechanism for its anticancer efficacy, largely due to the support of downstream intracellular pathway aberrations in response to this imbalanced redox environment.…”

“…The DOX-induction of ROS may provide a secondary mechanism for its anticancer efficacy, largely due to the support of downstream intracellular pathway aberrations in response to this imbalanced redox environment. These can include iron dysregulation, chromatin damage, metabolic changes and the induction of regulated cell death pathways [ 161 , 165 , 166 ].…”

How Shilajit-Based Nanocarriers Alter Classical Doxorubicin Delivery to Breast Cancer Cells (MCF-7 and ZR-75-1)

“…5 The accumulation of reactive oxygen species (ROS) is a major contributor to the cardiotoxicity of Dox. 6 Drug resistance is considered the other main obstacle to Dox clinical use. 7 Successful management of Dox-induced drug resistance and its side effects will positively influence treatment outcomes.…”