RETRACTED ARTICLE: Lapatinib induces mitochondrial dysfunction to enhance oxidative stress and ferroptosis in doxorubicin-induced cardiomyocytes via inhibition of PI3K/AKT signaling pathway

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Abstract
Lapatinib (LAP) is an important anti-cancer drug and is frequently alongside doxorubicin (DOX) as a combination therapy for better anti-cancer efficacy. However, many studies have reported that LAP in combination with DOX may induce highly cardiotoxicity. Accordingly, we aimed to explore the potential mechanism involved in the synergistic effect of LAP in DOX-induced cardiotoxicity. Here, cell counting kit-8 was used to detect cell viability and lactate dehydrogenase measurement was performed to assess cell injury. Cell apoptosis was evaluated by TUNEL assay and western blot assay. Mitochondrial dysfunction was identified by JC-1 assay, adenosine triphosphate (ATP) and Cytochrome C. Moreover, the activity of ROS, SOD, CAT and GSH were measured to elucidate oxidative stress level. Ferroptosis was examined by levels of Fe2+, GPX4 and ASCL4. Expressions of PI3K/AKT signaling were identified by western blot assay. The results revealed that LAP inhibited the cell viability and exacerbated cell injury induced by Dox, as well as increased cell apoptosis. LAP aggravated DOX-induced mitochondria damage by changed mitochondrial membrane potential, decreased ATP and increased level of Cytochrome C. In addition, the combination of LAP and DOX induced oxidative stress and ferroptosis in H9c2 cells. The activation of PI3K/AKT signaling reversed the detrimental effects of LAP on DOX-induced H9c2 cells. The data in this study showed for the first time that LAP aggravated Dox-induced cardiotoxicity by promoting oxidative stress and ferroptosis in cardiomyocytes via PI3K/AKT-mediated mitochondrial dysfunction, suggesting that PI3K/AKT activation is a promising cardioprotective strategy for DOX /LAX combination therapies.
Funding Information
  • Natural Science Foundation of Shaanxi Province (2019JM-523)

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