ReferenceID 265
The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II
Cell Death Dis
Mitochondria play a pivotal role in cancer bioenergetics and are considered a potential target for anticancer therapy. Considering the limited efficacy and toxicity of currently available mitochondria-targeting agents, i
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- Reference Id
- 265
- Evidence Id
- 16855
- Core Evidence Id
- 16855
- Source Reference Id
- 497
- Herb2 Reference Id
- HBREF000841
- Subject Paper Key
- HBIN028360_31649278
- Pubmed Id
- 31649278
- Doi
- 10.1038/s41419-019-2041-z
- Paper Title
- The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II
- Paper Abstract
- Mitochondria play a pivotal role in cancer bioenergetics and are considered a potential target for anticancer therapy. Considering the limited efficacy and toxicity of currently available mitochondria-targeting agents, it is necessary to develop effective mitochondria-targeting anticancer drugs. By screening a large chemical library consisting of natural products with diverse chemical entities, we identified gracillin, a steroidal saponin, as a mitochondria-targeting antitumor drug. Gracillin displayed broad-spectrum inhibitory effects on the viability of a large panel of human cancer cell lines, including those carrying acquired resistance to chemotherapy or EGFR-targeting drugs, by inducing apoptosis. We show that gracillin attenuates mitochondria-mediated cellular bioenergetics by suppressing ATP synthesis and by producing reactive oxygen species (ROS). Mechanistically, gracillin disrupts complex II (CII) function by abrogating succinate dehydrogenase (SDH) activity without affecting the succinate:ubiquinone reductase. The gracillin-induced cell death was potentiated by 3-nitropropionic acid (3-NPA) or thenoyltrifluoroacetone (TTFA), which inhibit CII by binding to the active site of SDHA or to the ubiquinone-binding site, respectively. Finally, we show that gracillin effectively suppressed the mutant-Kras-driven lung tumorigenesis and the growth of xenograft tumors derived from cell lines or patient tissues. Gracillin displayed no obvious pathophysiological features in mice. Collectively, gracillin has potential as a CII-targeting antitumor drug.
- Journal
- Cell Death Dis
- Publish Year
- 2019
- Experiment Subject
- human cancer cell lines
- Experiment Type
- Cell Experiment
- Phenotype Related
- Cancer
- Paper Title Cn
- Paper Title En
- The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II
- Bilingual Status
- semi_complete