期刊
FASEB JOURNAL
卷 34, 期 1, 页码 1447-1464出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201901467R
关键词
breast cancer; ellipticine; lung cancer; mitochondrial dynamics; mitochondrial division inhibitor 1 (mdivi-1); mitochondrial fission; right ventricle
资金
- Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)
- HHS | National Institutes of Health (NIH) [NIH-R01-HL071115, 1RC1HL099462]
- Canada Research Chairs (Chaires de recherche du Canada) [950-229252]
- Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC)
- Canadian Vascular Network
Mitochondrial fission is important in physiological processes, including coordination of mitochondrial and nuclear division during mitosis, and pathologic processes, such as the production of reactive oxygen species (ROS) during cardiac ischemia-reperfusion injury (IR). Mitochondrial fission is mainly mediated by dynamin-related protein 1 (Drp1), a large GTPase. The GTPase activity of Drp1 is essential for its fissogenic activity. Therefore, we aimed to identify Drp1 inhibitors and evaluate their anti-neoplastic and cardioprotective properties in five cancer cell lines (A549, SK-MES-1, SK-LU-1, SW 900, and MCF7) and an experimental cardiac IR injury model. Virtual screening of a chemical library revealed 17 compounds with high predicted affinity to the GTPase domain of Drp1. In silico screening identified an ellipticine compound, Drpitor1, as a putative, potent Drp1 inhibitor. We also synthesized a congener of Drpitor1 to remove the methoxymethyl group and reduce hydrolytic lability (Drpitor1a). Drpitor1 and Drpitor1a inhibited the GTPase activity of Drp1 without inhibiting the GTPase of dynamin 1. Drpitor1 and Drpitor1a have greater potency than the current standard Drp1 GTPase inhibitor, mdivi-1, (IC50 for mitochondrial fragmentation are 0.09, 0.06, and 10 mu M, respectively). Both Drpitors reduced proliferation and induced apoptosis in cancer cells. Drpitor1a suppressed lung cancer tumor growth in a mouse xenograft model. Drpitor1a also inhibited mitochondrial ROS production, prevented mitochondrial fission, and improved right ventricular diastolic dysfunction during IR injury. In conclusion, Drpitors are useful tools for understanding mitochondrial dynamics and have therapeutic potential in treating cancer and cardiac IR injury.
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