Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes

Area of Science:

• Cardiovascular Research
• Cancer Therapeutics
• Mitochondrial Biology

Background:

• Cardiovascular diseases are a significant concern for cancer patients undergoing treatment.
• The mechanisms underlying cancer drug-induced cardiotoxicity, particularly for targeted therapies like osimertinib, are not fully understood.
• Mitochondrial dysfunction plays a critical role in heart energy metabolism and is implicated in cardiotoxicity.

Purpose of the Study:

• To investigate the impact of anti-cancer drugs on mitochondrial quality control in cardiomyocytes.
• To elucidate the cardiotoxic mechanisms of osimertinib and identify potential protective strategies.
• To evaluate the role of sulfur metabolism in mitigating anti-cancer drug-induced cardiotoxicity.

Main Methods:

• Utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model cancer drug effects.
• Assessed the impact of osimertinib and doxorubicin on cardiomyocyte respiratory function and mitochondrial morphology (fission).
• Investigated the protective effects of inorganic sulfur donors (Na2S, Na2S2, Na2S3) against drug-induced cardiotoxicity.

Main Results:

• Osimertinib and doxorubicin caused concentration-dependent impairment of respiratory function and mitochondrial fission in hiPSC-CMs.
• Trastuzumab and cisplatin did not exhibit significant cardiotoxic effects under the tested conditions.
• Sodium sulfide (Na2S) attenuated osimertinib-induced cardiotoxicity by preventing the decrease in intracellular reduced sulfur levels.
• Na2S did not protect against doxorubicin-induced cardiotoxicity.

Conclusions:

• Osimertinib induces cardiotoxicity through mechanisms involving mitochondrial dysfunction and impaired sulfur metabolism.
• Inorganic sulfides, particularly Na2S, show promise as a potential therapeutic strategy to mitigate osimertinib-induced cardiotoxicity.
• Further research into precision pharmacotherapy using inorganic sulfides could offer new avenues for managing cancer treatment side effects.