Life sciences · 2025
SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
СтатьяНазвание и аннотация: Перевод в очереди
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Saroj Neha, Dholaniya Pankaj Singh, Alvi Syed Baseeruddin, Sridharan Divya, Soni Navisha, Ashraf Syed Abdullah, Choudhry Ayza, Ashraf Yusuf Ali, Mikula Sarah Kathleen, Singla Dinender Kumar, Khan Mahmood
Аннотация
AIMS: Doxorubicin (Dox) is a potent chemotherapeutic agent, but its use is limited by cardiotoxicity, primarily due to the disruption of Topoisomerase-2 beta (TOP2B) activity. Dexrazoxane (Dex), an FDA-approved cardioprotective drug, alleviates Dox-induced toxicity but lacks heart-specific targeting. This study investigates siRNA-mediated TOP2B knockdown as a more targeted strategy to protect cardiomyocytes from Dox-induced damage.
MATERIALS AND METHODS: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with siRNA to knock down TOP2B and were then exposed to Dox. We compared the cardioprotective effects of siRNA-mediated knockdown to Dex treatment using cell viability, cell toxicity assay and electrophysiological evaluation was performed using a multielectrode array (MEA).
KEY FINDINGS: Our results demonstrate that TOP2B silencing significantly decreases apoptosis and improved cell viability, as compared to the Dex treatment. Additionally, electrophysiological assays using a Multielectrode Array (MEA) demonstrated enhanced contractility and conductivity in siRNA-treated hiPSC-CMs. Furthermore, transmission electron microscopy (TEM) data revealed that TOP2B knockdown preserves mitochondrial morphology and sarcomere structure, compared to Dox and Dex-treated groups.
SIGNIFICANCE: These findings suggest that siRNA-mediated TOP2B inhibition could provide a safer, more specific approach to mitigate Dox-induced cardiotoxicity.
MATERIALS AND METHODS: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with siRNA to knock down TOP2B and were then exposed to Dox. We compared the cardioprotective effects of siRNA-mediated knockdown to Dex treatment using cell viability, cell toxicity assay and electrophysiological evaluation was performed using a multielectrode array (MEA).
KEY FINDINGS: Our results demonstrate that TOP2B silencing significantly decreases apoptosis and improved cell viability, as compared to the Dex treatment. Additionally, electrophysiological assays using a Multielectrode Array (MEA) demonstrated enhanced contractility and conductivity in siRNA-treated hiPSC-CMs. Furthermore, transmission electron microscopy (TEM) data revealed that TOP2B knockdown preserves mitochondrial morphology and sarcomere structure, compared to Dox and Dex-treated groups.
SIGNIFICANCE: These findings suggest that siRNA-mediated TOP2B inhibition could provide a safer, more specific approach to mitigate Dox-induced cardiotoxicity.