2. Academic Validation
  3. The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II

The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II

  • Cell Death Dis. 2019 Oct 24;10(11):810. doi: 10.1038/s41419-019-2041-z.
Hye-Young Min 1 2,  Hyun-Ji Jang 1,  Kwan Hee Park 1 3,  Seung Yeob Hyun 1,  So Jung Park 1,  Ji Hye Kim 4,  Jaekyoung Son 4,  Sam Sik Kang 3,  Ho-Young Lee 5 6 7
Affiliations

Affiliations

  • 1 Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  • 4 Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
  • 5 Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. hylee135@snu.ac.kr.
  • 6 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. hylee135@snu.ac.kr.
  • 7 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea. hylee135@snu.ac.kr.
PMID: 31649278 DOI: 10.1038/s41419-019-2041-z
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.

Figures
Products