Cleistanthin A derivative disrupts autophagy and suppresses head and neck squamous cell carcinoma progression via targeted vacuolar ATPase.
Humans
Autophagy
/ drug effects
Vacuolar Proton-Translocating ATPases
/ metabolism
Squamous Cell Carcinoma of Head and Neck
/ drug therapy
Cell Line, Tumor
Head and Neck Neoplasms
/ drug therapy
Cisplatin
/ pharmacology
Cell Movement
/ drug effects
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Lysosomes
/ drug effects
Epithelial-Mesenchymal Transition
/ drug effects
Cell Proliferation
/ drug effects
Cathepsin D
/ metabolism
Anticancer
Autophagy
Cleistanthin A derivative
Head and neck squamous cell carcinoma
Vacuolar ATPase
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 Sep 2024
29 Sep 2024
Historique:
received:
18
05
2024
accepted:
16
09
2024
medline:
30
9
2024
pubmed:
30
9
2024
entrez:
29
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39343784
doi: 10.1038/s41598-024-73186-1
pii: 10.1038/s41598-024-73186-1
doi:
Substances chimiques
Vacuolar Proton-Translocating ATPases
EC 3.6.1.-
Cisplatin
Q20Q21Q62J
Antineoplastic Agents
0
Cathepsin D
EC 3.4.23.5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
22582Subventions
Organisme : National Research Council of Thailand (NRCT) and Mahidol University
ID : N42A660523
Organisme : National Research Council of Thailand (NRCT) and Mahidol University
ID : N42A660523
Informations de copyright
© 2024. The Author(s).
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