Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene
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, lapatin...
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| author | Kiyomu Fujii Rina Fujiwara-Tani Shota Nukaga Hitoshi Ohmori Yi Luo Ryoichi Nishida Takamitsu Sasaki Yoshihiro Miyagawa Chie Nakashima Isao Kawahara Ruiko Ogata Ayaka Ikemoto Rika Sasaki Hiroki Kuniyasu |
| author_facet | Kiyomu Fujii Rina Fujiwara-Tani Shota Nukaga Hitoshi Ohmori Yi Luo Ryoichi Nishida Takamitsu Sasaki Yoshihiro Miyagawa Chie Nakashima Isao Kawahara Ruiko Ogata Ayaka Ikemoto Rika Sasaki Hiroki Kuniyasu |
| author_sort | Kiyomu Fujii |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-25T00:27:35Z |
| format | Article |
| id | doaj.art-499f30265ecb4415ac43fd9caf3cf384 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-25T00:27:35Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-499f30265ecb4415ac43fd9caf3cf3842024-03-12T16:47:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01255301510.3390/ijms25053015Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of PterostilbeneKiyomu Fujii0Rina Fujiwara-Tani1Shota Nukaga2Hitoshi Ohmori3Yi Luo4Ryoichi Nishida5Takamitsu Sasaki6Yoshihiro Miyagawa7Chie Nakashima8Isao Kawahara9Ruiko Ogata10Ayaka Ikemoto11Rika Sasaki12Hiroki Kuniyasu13Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanPatients 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.https://www.mdpi.com/1422-0067/25/5/3015drug-induced cardiac damageferroptosismitochondrial damagemitochondrial ironpterostilbeneantioxidants |
| spellingShingle | Kiyomu Fujii Rina Fujiwara-Tani Shota Nukaga Hitoshi Ohmori Yi Luo Ryoichi Nishida Takamitsu Sasaki Yoshihiro Miyagawa Chie Nakashima Isao Kawahara Ruiko Ogata Ayaka Ikemoto Rika Sasaki Hiroki Kuniyasu Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene International Journal of Molecular Sciences drug-induced cardiac damage ferroptosis mitochondrial damage mitochondrial iron pterostilbene antioxidants |
| title | Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene |
| title_full | Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene |
| title_fullStr | Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene |
| title_full_unstemmed | Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene |
| title_short | Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene |
| title_sort | involvement of ferroptosis induction and oxidative phosphorylation inhibition in the anticancer drug induced myocardial injury ameliorative role of pterostilbene |
| topic | drug-induced cardiac damage ferroptosis mitochondrial damage mitochondrial iron pterostilbene antioxidants |
| url | https://www.mdpi.com/1422-0067/25/5/3015 |
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