Metabolic targeting of cancer by a ubiquinone uncompetitive inhibitor of mitochondrial complex I
| Autor: | Cheng Hu, Philippe Marchetti, Yabin Cheng, Arkadii Vaisburg, Dieter A. Wolf, Elke Holinski-Feder, Matthias Bureik, Alexandre Rosa Campos, Jochen Maurer, Guangcheng Luo, Shashi Jain, Adriana Charbono, Guiyou Tian, Andreas Bleilevens, Elmar Stickeler, Jerome Kluza, Wei Ke, Madalina Giurgiu |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Electron Transport Complex I Cytochrome Ubiquinone Protein subunit NDUFS2 Clinical Biochemistry Cancer Biology medicine.disease Biochemistry Cell biology Mitochondria chemistry Cancer stem cell Oxidoreductase Neoplasms Drug Discovery Cancer cell medicine biology.protein Molecular Medicine Uncompetitive inhibitor Molecular Biology |
| Zdroj: | Cell chemical biology. 29(3) |
| ISSN: | 2451-9448 |
| Popis: | Summary SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through an as-yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, complex I [CI]). Instead of affecting the quinone-binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple-negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer. |
| Databáze: | OpenAIRE |
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