Abstract
Cardiovascular disease and cancer are the leading causes of death in developed societies. Despite their effectiveness, many cancer therapies exhibit deleterious cardiovascular side effects such as cardiotoxicity and heart failure. The cardiotoxic effects of anthracyclines such as doxorubicin are the most well-characterized of cardiotoxic anti-cancer therapies. While other anti-neoplastic drugs also induce cardiotoxicity, often leading to heart failure, they are beyond the scope of this review. This review first summarizes the mechanisms of doxorubicin-induced cardiotoxicity. It then reviews emerging preclinical evidence that high density lipoprotein and its precursor protein apolipoprotein A1, which are known for their protective effects against ischemic cardiovascular disease, may also protect against doxorubicin-induced cardiotoxicity both directly and indirectly, when used therapeutically.
Highlights
Advances in cancer treatment over the past few decades have led to substantial increases in cancer survivorship [1, 2]
In addition to research showing that High density lipoproteins (HDL) can protect cardiomyocytes from chemotherapy-induced cytotoxicity both directly by inducing survival signaling in the cardiomyocytes, and indirectly by acting as a targeted delivery system for anticancer agents, sparing the heart, other research has suggested that HDL and its precursor apolipoprotein A1 (ApoA1) may have direct anti-tumor effects themselves
Preclinical studies suggest that HDL targeted therapies involving pharmacological treatment with supra-physiological levels of ApoA1, peptides based on ApoA1 (ApoA1 mimetic peptides) or reconstituted HDL (rHDL) like particles may show promise in the protection against chemotherapy related cardiotoxicity via a number of mechanisms (Figure 4)
Summary
Advances in cancer treatment over the past few decades have led to substantial increases in cancer survivorship [1, 2]. Anthracyclines such as doxorubicin (DOX) are, perhaps, the most well-studied cardiotoxic chemotherapeutic agents They have a number of direct cardiotoxic effects, including DNA damage, interfering with mitochondrial function, induction of reactive oxygen species (ROS), alterations in autophagy and induction in apoptosis. We will review recent advances in our understanding of HDL functions and properties that can be exploited to mitigate DOX-associated cardiotoxicity These include understanding the mechanisms by which HDL induces cytoprotective responses in cells including cardiomyocytes, the ability of HDL and synthetic particles based on it to encapsulate DOX and serve as delivery vehicles, and findings that therapeutic treatment with HDL’s major structural protein, apolipoprotein A1 (ApoA1) appears to have direct antineoplastic effects in preclinical tumor models [32,33,34]
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