Abstract
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.
Highlights
Hepatocellular carcinoma (HCC), known as liver cancer, is one of the most common malignant tumors of the liver
Deptropine inhibited cell proliferation in dose- and time-dependent manners (Figure 2). These results suggested that deptropine and several other benzocycloheptene structural analogue drugs have cytotoxic activity against human hepatoma cells
To understand why the SQSTM1/p62 protein accumulated in HepG2 cells and was not degraded in Hep3B cells, we investigated whether deptropine could block autophagic flux in hepatoma cells by transfecting cells with the mCherry-green fluorescent protein (GFP)-LC3 tandem reporter plasmid
Summary
Hepatocellular carcinoma (HCC), known as liver cancer, is one of the most common malignant tumors of the liver. It has higher incidences in Asian countries, such as Taiwan, China, and Japan, and relatively low incidences in Western countries. HCC is the second leading cause of cancer-related deaths in Taiwan and the fourth leading cause of cancer-related deaths worldwide [1,2]. The main causes of HCC are related to hepatitis B, hepatitis C, alcoholic liver disease, non-alcoholic fatty liver disease, and cirrhosis [3,4]. Surgical resection and liver transplantation are curative treatments for these patients. There is no ideal chemotherapeutic drug to treat patients with HCC
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