Mechanism studies on anti-HepG2 cell proliferation of phenanthroline derivatives as G-quadruplex DNA stabilizers

In our previous study, two similar phenanthroline derivatives (1 and 2) were confirmed to be potent and selective stabilizers of the G-quadruplex DNAs of c-myc promoter and human telomere in vitro. In this study, we investigated the anti-proliferative mechanism of both ligands to HepG2 cells. MTT assay indicated that IC50 values are 1.26 and 0.5 μM for 1 and 2, respectively. Flow cytometric assays showed that both ligands could induce cell apoptosis, and 1 could arrest cell cycle in S and G2/M phases whereas the cell cycle was arrested in G0/G1 phase for 2, which are attributed to the expression decreases of the key regulating proteins cyclin B1/Cdk1 and cyclin D1/Cdk4 in the G2/M and G0/G1 phases, respectively. Both ligands could inhibit the transcription of c-myc gene and down-regulate the expression of c-myc, Sp1, and hTERT protein but up-regulate the p53 protein expression. 2 performed higher inhibitory activity than 1. Furthermore, both 1 and 2 had no effect on the elongation of telomeric DNA. The current results suggested that the decreases of c-myc, Sp1, and hTERT expressions and the increase of p53 expression, together with the reduction of cyclins/Cdks proteins in the regulation of the cell cycle, and/or the telomeric chromatin alteration led to cell cycle arrest, apoptosis, and growth inhibition induced by both ligands.

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