The Antihistamine Deptropine Induces Hepatoma Cell Death through Blocking Autophagosome-Lysosome Fusion

Area of Science:

• Pharmacology
• Oncology
• Cell Biology

Background:

• Antihistamines show potential antitumor effects, but their mechanisms against hepatocellular carcinoma (HCC) are unclear.
• Hepatocellular carcinoma proliferation requires further investigation into novel therapeutic targets.

Purpose of the Study:

• To investigate the antiproliferative effects of benzocycloheptene analogues on human hepatoma cells.
• To elucidate the underlying mechanisms of deptropine-induced inhibition of HCC proliferation, focusing on autophagy.

Main Methods:

• Screening of 12 benzocycloheptene analogues for antiproliferation activity against Hep3B and HepG2 cells.
• Analysis of autophagy-related protein expression (LC3B-II, SQSTM1/p62, ATG7, VPS34, AMPK, Akt) and cathepsin L processing.
• Immunofluorescence microscopy to assess autophagosome formation and lysosome fusion.
• In vivo efficacy study using a xenograft nude mice model with Hep3B tumors.

Main Results:

• Deptropine demonstrated potent inhibition of Hep3B and HepG2 cell proliferation.
• Deptropine increased LC3B-II expression and autophagosome accumulation but blocked autophagosome-lysosome fusion.
• Deptropine inhibited cathepsin L maturation and did not alter key autophagy proteins (ATG7, VPS34, AMPK, Akt).
• Deptropine significantly suppressed Hep3B tumor growth in vivo.

Conclusions:

• Deptropine exhibits significant in vitro and in vivo antitumor activity against hepatocellular carcinoma.
• The mechanism involves the induction of autophagy blockade by inhibiting autophagosome-lysosome fusion.
• Deptropine represents a potential therapeutic agent for liver cancer treatment.