Amantadine inhibits cellular proliferation and induces the apoptosis of hepatocellular cancer cells in vitro

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide, and its incidence associated with viral infection has increased in recent years. Amantadine is a tricyclic symmetric amine that can effectively protect against the hepatitis C virus. However, its antitumor properties remain unclear. In the present study, the effects of amantadine on tumor cell viability, cell cycle regulation and apoptosis were investigated. The growth of HepG2 and SMMC‑7721 cells (HCC cell lines) was detected by an MTT assay. Flow cytometry was used to investigate cell cycle regulation and apoptosis. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were also performed to examine the expression of cell cycle‑ and apoptosis‑related genes and proteins, including cyclin E, cyclin D1, cyclin‑dependent kinase 2 (CDK2), B‑cell lymphoma 2 (Bcl‑2) and Bax. Our results demonstrated that amantadine markedly inhibited the proliferation of HepG2 and SMMC‑7721 cells in a dose‑ and time‑dependent manner and arrested the cell cycle at the G0/G1 phase. The levels of the cell cycle‑related genes and proteins (cyclin D1, cyclin E and CDK2) were reduced by amantadine, and apoptosis was significantly induced. Amantadine treatment also reduced Bcl‑2 and increased the Bax protein and mRNA levels. Additionally, Bcl‑2/Bax ratios were lower in the two HCC cell lines following amantadine treatment. Collectively, these results emphasize the role of amantadine in suppressing proliferation and inducing apoptosis in HCC cells, advocating its use as a novel tumor-suppressive therapeutic candidate.

Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer

“…Amantadine, which acts on the viral M2 protein, thus hindering virus uncoating once it is taken inside the cell by endocytosis, was previously reported to suppress proliferation and to induce apoptosis in hepatocellular carcinoma cells [ 121 ]. Pleconaril integrates into the capsid of picornaviruses, preventing the virus from attaching to cellular receptors and preventing RNA release into the cell [ 122 ].…”

Copper-Based Complexes with Adamantane Ring-Conjugated bis(3,5-Dimethyl-pyrazol-1-yl)acetate Ligand as Promising Agents for the Treatment of Glioblastoma

“…In the present study, the bifunctional species L 2 H has been conjugated to the known drug amantadine to obtain the new ligand L 2Ad , which has been used as a chelator for the synthesis of the new Cu complexes 1 – 5 (Figure ) to be evaluated as potential agents for the treatment of glioblastoma. Amantadine was selected as a bioactive molecule since it has recently been demonstrated to show from moderate to good antiproliferative effects in different human tumor cell lines, including hepatocarcinoma, melanoma, and glioblastoma cells. − Moreover, Pt-based complexes functionalized with amantadine have already been reported to display promising cytotoxic activity against various human tumor cell lines . Finally, amantadine consists of a primary amine group suitable to be conjugated to the carboxylic group of the bifunctionalizable species L 2 H and the bioversatile adamantyl scaffold, which characterizes several derivatives identified as anticancer agents. , …”

Anticancer Activity of Amantadine and Evaluation of Its Interactions with Selected Cytostatics in Relation to Human Melanoma Cells

“…Amantadine increased the expression of aromatic amino acid decarboxylase (AADC) [ 12 ]. In vitro experiments revealed that amantadine inhibits proliferation of HepG2 and SMMC-7721 cells by arresting the cell cycle at the G0/G1 phase [ 13 ]. Amantadine also reduces Bcl-2 and increases Bax proteins and mRNA levels in HepG2 and SMMC-7721 cell lines, which leads to the intensification of apoptosis in liver cancer cells [ 13 ].…”

“…In vitro experiments revealed that amantadine inhibits proliferation of HepG2 and SMMC-7721 cells by arresting the cell cycle at the G0/G1 phase [ 13 ]. Amantadine also reduces Bcl-2 and increases Bax proteins and mRNA levels in HepG2 and SMMC-7721 cell lines, which leads to the intensification of apoptosis in liver cancer cells [ 13 ]. Amantadine seems to be a drug with potential anti-cancer activity due to the fact that the drug could inhibit cell growth by modulating cyclin D1, cyclin E, CDK2 and inducing apoptosis via regulation of Bax and Bcl-2 proteins [ 13 ].…”