Abstract
Cardiotoxicity is a major cause of high attrition rates among newly developed drugs. Moreover, anti-cancer treatment-induced cardiotoxicity is one of the leading reasons of mortality in cancer survivors. Cardiotoxicity screening in vitro may improve predictivity of cardiotoxicity by novel drugs, using human pluripotent stem cell (hPSC)-derived-cardiomyocytes. Anthracyclines, including Doxorubicin, are widely used and highly effective chemotherapeutic agents for the treatment of different forms of malignancies. Unfortunately, anthracyclines cause many cardiac complications early or late after therapy. Anthracyclines exhibit their potent anti-cancer effect primarily via induction of DNA damage during the DNA replication phase in proliferative cells. In contrast, studies in animals and hPSC-cardiomyocytes have revealed that cardiotoxic effects particularly arise from (1) the generation of oxidative stress inducing mitochondrial dysfunction, (2) disruption of calcium homeostasis, and (3) changes in transcriptome and proteome, triggering apoptotic cell death. To increase the therapeutic index of chemotherapeutic Doxorubicin therapy several protective strategies have been developed or are under development, such as (1) reducing toxicity through modification of Doxorubicin (analogs), (2) targeted delivery of anthracyclines specifically to the tumor tissue or (3) cardioprotective agents that can be used in combination with Doxorubicin. Despite continuous progress in the field of cardio-oncology, cardiotoxicity is still one of the major complications of anti-cancer therapy. In this review, we focus on current hPSC-cardiomyocyte models for assessing anthracycline-induced cardiotoxicity and strategies for cardioprotection. In addition, we discuss latest developments toward personalized advanced pre-clinical models that are more closely recapitulating the human heart, which are necessary to support in vitro screening platforms with higher predictivity. These advanced models have the potential to reduce the time from bench-to-bedside of novel antineoplastic drugs with reduced cardiotoxicity.
Highlights
Cardiovascular diseases and cancer are the two leading causes of death in industrialized countries
Anthracyclines are a group of widely used anti-cancer drugs that are known to cause cardiac complications, either early or late after start of treatment [1,2,3,4,5,6,7]
In approximately 11% of patients, Doxorubicin-induced cardiotoxicity leads to an acute response within 2–3 days of administration, manifested by chest pain resulting from different forms of arrhythmia [3]
Summary
Cardiovascular diseases and cancer are the two leading causes of death in industrialized countries. We will discuss the potential to use hPSC-derived cardiac models for improved safety assessment of anti-cancer drugs and strategies to overcome current limitations for developing in vitro drug testing platforms with a higher predictivity. Several studies in hPSC-cardiomyocytes have shown that mitochondrial dysfunction, disruption of calcium homeostasis, as well as altered gene and protein expression levels triggering apoptotic cell death, play important roles in anthracycline-induced cardiotoxicity (Figure 1).
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