Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene.
Kiyomu FujiiRina Fujiwara-TaniShota NukagaHitoshi OhmoriYi LuoRyoichi NishidaTakamitsu SasakiYoshihiro MiyagawaChie NakashimaIsao KawaharaRuiko OgataAyaka IkemotoRika SasakiHiroki KuniyasuPublished in: International journal of molecular sciences (2024)
Patients with cancer die from cardiac dysfunction second only to the disease itself. Cardiotoxicity caused by anticancer drugs has been emphasized as a possible cause; however, the details remain unclear. To investigate this mechanism, we treated rat cardiomyoblast H9c2 cells with sunitinib, lapatinib, 5-fluorouracil, and cisplatin to examine their effects. All anticancer drugs increased ROS, lipid peroxide, and iron (II) levels in the mitochondria and decreased glutathione peroxidase-4 levels and the GSH/GSSG ratio. Against this background, mitochondrial iron (II) accumulates through the unregulated expression of haem oxygenase-1 and ferrochelatase. Anticancer-drug-induced cell death was suppressed by N-acetylcysteine, deferoxamine, and ferrostatin, indicating ferroptosis. Anticancer drug treatment impairs mitochondrial DNA and inhibits oxidative phosphorylation in H9c2 cells. Similar results were observed in the hearts of cancer-free rats treated with anticancer drugs in vitro. In contrast, treatment with pterostilbene inhibited the induction of ferroptosis and rescued the energy restriction induced by anticancer drugs both in vitro and in vivo. These findings suggest that induction of ferroptosis and inhibition of oxidative phosphorylation are mechanisms by which anticancer drugs cause myocardial damage. As pterostilbene ameliorates these mechanisms, it is expected to have significant clinical applications.
Keyphrases
- drug induced
- cell death
- liver injury
- cell cycle arrest
- mitochondrial dna
- oxidative stress
- induced apoptosis
- squamous cell carcinoma
- emergency department
- poor prognosis
- adverse drug
- cell proliferation
- protein kinase
- reactive oxygen species
- magnetic resonance imaging
- nitric oxide
- papillary thyroid
- signaling pathway
- endoplasmic reticulum stress
- binding protein
- smoking cessation
- fatty acid
- pi k akt
- mouse model
- replacement therapy
- squamous cell