Abstract
BackgroundApigenin (4′,5,7-trihydroxyflavone, AP), an active component of many medicinal Chinese herbs, exhibits anticancer properties in vitro and in vivo. This study aims to investigate the genotoxic, cytostatic, and cytotoxic effects of AP and time course changes in the levels of anti- and pro-apoptotic proteins involved in the DNA damage response in HepG2 cells.MethodsThe genotoxic potential of AP was determined by sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) analysis. The levels of cytostaticity and cytotoxicity were evaluated by the proliferation rate and mitotic indices, respectively. MTT was used to study cytotoxicity, while the induction of apoptosis and the expression of apoptosis-related proteins were determined by ELISA.ResultsAt concentrations greater than 10 μM, AP decreased cell survival in a dose- (48 h: 10 vs. 20 μΜ, P < 0.001 and 20 vs. 50 μΜ, P = 0.005; 72 h: 10 vs. 20 μΜ, P < 0.001 and 20 vs. 50 μΜ, P = 0.001) and time-dependent manner (20 μΜ: 24 vs. 48 h, P < 0.001 and 48 vs. 72 h, P = 0.003; 50 μΜ: 24 vs. 48 h, P < 0.001 and 48 vs. 72 h, P < 0.001; 100 μΜ: 24 vs. 48 h, P < 0.001 and 48 vs. 72 h, P < 0.001). SCEs rates, cell proliferation, and mitotic divisions were also affected in a dose-dependent manner (P < 0.001). There was no change in the frequency of aberrant cells (1 μΜ ΑP: P = 0.554; 10 μM AP: P = 0.337; 20 μΜ AP: P = 0.239). Bcl-2 levels were reduced 3 h after AP administration (P = 0.003) and remained reduced throughout the 48 h observation period (6 h, P = 0.044; 12 h, P = 0.001; 24 h, P = 0.042; 48 h, P = 0.012). Bax and soluble Fas exhibited a transient upregulation 24 h after AP treatment. The Bax/Bcl-2 ratio was also increased at 12 h and remained increased throughout the 48 h observation period.ConclusionAP exhibited dose-dependent genotoxic potential in HepG2 cells. The protein levels of sFas, Bcl-2, and Bax were affected by AP to promote cell survival and cell death, respectively.
Highlights
Apigenin (4′,5,7-trihydroxyflavone, AP), an active component of many medicinal Chinese herbs, exhibits anticancer properties in vitro and in vivo
We investigated the proliferation rate index (PRI) and the mitotic index (MI), markers of the cytostatic and cytotoxic properties of chemical and physical agents, respectively [49]
Similar results were reported by Chiang et al [25] and Choi et al [27], who studied the antiproliferative effect of AP in HepG2 cells
Summary
Apigenin (4′,5,7-trihydroxyflavone, AP), an active component of many medicinal Chinese herbs, exhibits anticancer properties in vitro and in vivo. This study aims to investigate the genotoxic, cytostatic, and cytotoxic effects of AP and time course changes in the levels of anti- and pro-apoptotic proteins involved in the DNA damage response in HepG2 cells. AP induced apoptosis in the hepatic parenchyma [24,25,26,27,28,29], and exhibited antiproliferative and apoptotic properties in HepG2, Hep3B and PLC/PRF/5 human liver cancer cell lines [25,26,27,28]. Generation of reactive oxygen species (ROS) might play an important role in AP-induced apoptosis by transcriptionally downregulating catalase activity and increasing hydrogen peroxide levels [27,28]. Cell death induction has been associated with Bax/Bcl-2 ratio changes, cytochrome c release, and Apaf-1 induction, leading to caspase activation and PARP-cleavage in leukemia, prostate carcinoma, lung cancer, and cervical carcinoma cells [19,30,31,32,33]
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