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Updated: Aug 18, 2025
High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
An efficient human stem cells derived cardiotoxicity testing platform for testing oncotherapeutic analogues of
Saurabh Mandal1, Naisarg Gamit1, Subhankar Biswas2
1Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560 065, India.
Abstract:
Oncotherapeutics research is progressing at a rapid pace, however, not many drugs complete the successful clinical trial because of severe off-target toxicity to cardiomyocytes which ultimately leads to cardiac dysfunction. It is thus important to emphasize the need for early testing for possible cardiotoxicity of emerging oncotherapeutics. In this study, we assessed a novel stem cell-derived cardiac model for testing for cardiotoxicity of novel oncotherapeutics. We evaluated the cardiotoxic effect of synthesized derivatives of oncotherapeutics, quercetin (QMJ-2, -5, and -6) and cinnamic acid (NMJ-1, -2, and -3) using human Wharton's jelly mesenchymal stem cells-derived cardiomyocytes (WJCM) against known cardiotoxic oncologic drugs, doxorubicin, 5-fluorouracil, cisplatin. QMJ-6, NMJ-2, and NMJ-3 were not cardiotoxic and had minimum cardiac side effects. They did not show any effect on cardiomyocyte viability, caused low LDH release, and intracellular ROS production kept the calcium flux minimal and protected the active mitochondrial status in cardiomyocytes. They persevered cardiac-specific gene expression as well. However, compounds QMJ-2, QMJ-5, and NMJ-1 were cardiotoxic and the concentration needs to be reduced to prevent toxic effects on cardiomyocytes. Significantly, we were able to demonstrate that WJCM is an efficient cardiac testing model to analyze the cardiotoxicity of drugs in a human context.
Insights
Novel cancer drugs face toxicity challenges. This study introduces a human stem cell-derived cardiac model to test oncotherapeutics, identifying safe compounds like QMJ-6, NMJ-2, and NMJ-3, and highlighting others needing dose reduction.
Area of Science:
- Cardiology
- Oncology
- Stem Cell Biology
Background:
- Oncotherapeutics development is hindered by cardiotoxicity, leading to clinical trial failures and cardiac dysfunction.
- Early assessment of cardiotoxicity is crucial for the successful clinical translation of novel anti-cancer drugs.
- Existing models may not fully recapitulate human cardiac physiology, necessitating improved testing platforms.
Purpose of the Study:
- To evaluate a novel human stem cell-derived cardiac model for assessing oncotherapeutic cardiotoxicity.
- To screen synthesized quercetin (QMJ-2, -5, -6) and cinnamic acid (NMJ-1, -2, -3) derivatives for cardiotoxic effects.
- To compare the efficacy of the novel model against established cardiotoxic drugs like doxorubicin.
Main Methods:
- Utilized human Wharton's jelly mesenchymal stem cells-derived cardiomyocytes (WJCM) as a cardiac model.
- Assessed cardiotoxicity by measuring cardiomyocyte viability, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production, calcium flux, and mitochondrial activity.
- Monitored cardiac-specific gene expression to evaluate drug impact on cardiomyocyte function.
Main Results:
- Compounds QMJ-6, NMJ-2, and NMJ-3 demonstrated no cardiotoxicity, exhibiting minimal cardiac side effects, low LDH release, and preserved mitochondrial function.
- These safe compounds maintained cardiac-specific gene expression and minimal intracellular ROS production and calcium flux.
- Compounds QMJ-2, QMJ-5, and NMJ-1 were identified as cardiotoxic, suggesting a need for concentration reduction to mitigate adverse effects.
Conclusions:
- The human WJCM model is an effective platform for analyzing drug-induced cardiotoxicity in a human context.
- Identified specific quercetin and cinnamic acid derivatives with a favorable safety profile for potential oncotherapeutic use.
- This model facilitates early detection of cardiotoxicity, potentially improving the success rate of oncotherapeutics in clinical trials.
