The Antihistamine Deptropine Induces Hepatoma Cell Death through Blocking Autophagosome-Lysosome Fusion.
LC3B
SQSTM1/p62
antihistamine
autophagy
deptropine
hepatoma
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
18 Jun 2020
18 Jun 2020
Historique:
received:
04
05
2020
revised:
14
06
2020
accepted:
16
06
2020
entrez:
24
6
2020
pubmed:
24
6
2020
medline:
24
6
2020
Statut:
epublish
Résumé
Some antihistamines have exhibited significant antitumor activity alone or in combination with other therapies in in vitro and clinical studies. However, the underlying mechanisms of how antihistamines inhibit hepatocellular carcinoma proliferation are still unknown. We first screened the antiproliferation activity of 12 benzocycloheptene structural-analogue drugs, and results showed that deptropine was the most potent inhibitor of both Hep3B and HepG2 human hepatoma cells. Deptropine significantly increased light chain 3B-II (LC3B-II) expression but did not induce sequestosome 1 (SQSTM1/p62) degradation in either cell line. Interestingly, other autophagy-related proteins, such as autophagy-related 7 (ATG7), vacuolar protein sorting 34 (VPS34), phosphorylated adenosine 5'-monophosphate-activated protein kinase (AMPK), and phosphorylated protein kinase B (PKB, also known as Akt), exhibited no significant change in either deptropine-treated cell line. Deptropine also inhibited the processing of cathepsin L from its precursor form to its mature form. Immunofluorescence microscopy showed an increase of autophagosomes in deptropine-treated cells, but deptropine blocked the fusion between autophagosomes and lysosomes. In a xenograft nude mice model, 2.5 mg/kg deptropine showed a great inhibitory effect on Hep3B tumor growth. These results suggest that deptropine can induce in vitro and in vivo hepatoma cell death, and the underlying mechanisms might be mediated through inhibiting autophagy by blocking autophagosome-lysosome fusion.
Identifiants
pubmed: 32570749
pii: cancers12061610
doi: 10.3390/cancers12061610
pmc: PMC7352610
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Ministry of Science and Technology of the Republic of China
ID : MOST 107-2320-B-038-023-MY3
Organisme : Wan Fang Hospital
ID : 106 TMU-WFH-07 and 107-TMU-WFH-9
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