2. Academic Validation
  3. Cleistanthin A derivative disrupts autophagy and suppresses head and neck squamous cell carcinoma progression via targeted vacuolar ATPase

Cleistanthin A derivative disrupts autophagy and suppresses head and neck squamous cell carcinoma progression via targeted vacuolar ATPase

  • Sci Rep. 2024 Sep 29;14(1):22582. doi: 10.1038/s41598-024-73186-1.
Anongnat Wongpan 1,  Wittaya Panvongsa 2,  Sucheewin Krobthong 3,  Bodee Nutho 4,  Phongthon Kanjanasirirat 5 6,  Kedchin Jearawuttanakul 5,  Tanawadee Khumpanied 5,  Sureeporn Phlaetita 7,  Napason Chabang 8,  Bamroong Munyoo 5 9,  Patoomratana Tuchinda 5 9,  Marisa Ponpuak 7,  Suparerk Borwornpinyo 5 10,  Arthit Chairoungdua 11 12 13
Affiliations

Affiliations

  • 1 Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd., Ratchathewi, Bangkok, 10400, Thailand.
  • 2 Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • 3 Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
  • 4 Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 5 Excellent Center for Drug Discovery (ECDD), Mahidol University, Bangkok, Thailand.
  • 6 Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 7 Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 8 School of Bioinnovation and Bio-Based Product Intelligence, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 9 Department of Chemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 10 Department of Biotechnology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 11 Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd., Ratchathewi, Bangkok, 10400, Thailand. arthit.chi@mahidol.ac.th.
  • 12 Excellent Center for Drug Discovery (ECDD), Mahidol University, Bangkok, Thailand. arthit.chi@mahidol.ac.th.
  • 13 Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand. arthit.chi@mahidol.ac.th.
PMID: 39343784 DOI: 10.1038/s41598-024-73186-1
Abstract

Head and neck squamous cell carcinoma (HNSCC) present a significant challenge due to its heterogeneity and limited treatment options, often resulting in severe side effects and poor survival rates with conventional chemoradiotherapy. Here, we investigated the Anticancer activity of halogenated benzoate derivatives of cleistanthin A, ECDD-S16 and ECDD-S18, in HNSCC cells. Our findings revealed that ECDD-S18 exhibited remarkable cytotoxicity, surpassing that of cisplatin with minimal impact on normal and cisplatin-sensitive cells. Notably, ECDD-S18 induced Apoptosis in a dose-dependent manner and effectively targeted vacuolar ATPase (V-ATPase), impairing lysosomal acidification. Intriguingly, ECDD-S18 inhibited autophagic flux, as evidenced by increased autophagosome but decreased autolysosome formation. Furthermore, proteomic analysis demonstrated downregulation of Cathepsin D (CTSD), the lysosomal protease in ECDD-S18-treated HNSCC cells, concurrent with suppressed cell migration. ECDD-S18 also decreased expression of mesenchymal markers, suggesting inhibition of epithelial-mesenchymal transition (EMT). Importantly, cotreatment with ECDD-S18 and cisplatin enhanced the reduction in cell viability. Collectively, our results indicated that the Anticancer activity of ECDD-S18 partly stems from its ability to disrupt lysosomal acidification and inhibit Autophagy via targeted inhibition of V-ATPase. These findings underscore the therapeutic promise of ECDD-S18 in HNSCC treatment, either alone or in combination with existing drugs, while mitigating toxicity to normal cells.

Keywords

Anticancer; Autophagy; Cleistanthin A derivative; Head and neck squamous cell carcinoma; Vacuolar ATPase.

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