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

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.

H1-Antihistamines Reduce the Risk of Hepatocellular Carcinoma in Patients With Hepatitis B Virus, Hepatitis C Virus, or Dual Hepatitis B Virus-Hepatitis C Virus Infection

“…51 In our previous cell model experiments, we observed that the administration of deptropine could inhibit the combination of autophagosome and lysosome and, ultimately, induce hepatoma cell death. 39 Although no mechanism have been discussed in the aforementioned studies, AH is nevertheless believed to have a role in immunoregulation. Moreover, unlike other anti-inflammatory drugs, AH can induce hepatoma cell death.…”

“…38 Our previous study demonstrated that deptropine (an AH) blocks the fusion of autophagosome and lysosome and, consequently, induced hepatoma cell death. 39 Zhao et al 40 revealed upregulation of histamine receptors promote tumor progression in HCC and He et al 41 found the possible antiviral effects of AHs in HCV. Despite the extensive application of targeted therapy, current treatments for advanced HCC remain unsatisfactory.…”

Efficacy of Cyproheptadine Monotherapy in Hepatocellular Carcinoma With Bone Metastasis: A Case Report

“…Cyproheptadine has cytotoxic effects and increased annexin V staining for cell death, which raise the levels of poly ADP-ribose polymerase (PARP) and its cleaved form, inducing apoptosis in HCC cell lines ( 3 , 7 , 11 ). In addition, cyproheptadine can suppress the PI3K/AKT signaling pathway in carcinoma cells and multiple myeloma cells, leading to cell cycle arrest in the G1 phase and G1/S transition, resulting in apoptosis and necrosis ( 7 , 12 ).…”

Cancer Stem Cell (CSC) Inhibitors in Oncology—A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives

“…130 In a recently concluded study, 13 induced hepatoma cell death by blocking autophagosome−lysososome fusion, that is, it initiated autophagy, but failed to complete its maturation. 131 In addition, 13 moderately activated caspase-3, -8, and -9 and partially contributed to the cell death via apoptosis activation. Furthermore, Hep3B tumor xenograft studies in athymic mice showed a significant reduction in the tumor volume, thereby supporting the in vitro observations.…”

“…It is an inhibitor of ALDH with potent activity against breast CSCs . In a recently concluded study, 13 induced hepatoma cell death by blocking autophagosome–lysososome fusion, that is, it initiated autophagy, but failed to complete its maturation . In addition, 13 moderately activated caspase-3, -8, and -9 and partially contributed to the cell death via apoptosis activation.…”