Zebularine induces prolonged apoptosis effects via the caspase-3/PARP pathway in head and neck cancer cells

Zebularine, a potent DNA methyltransferase inhibitor, is potentially able to influence gene regulation and thereby alters cell behavior. This study illustrates the effect of zebularine on human squamous cell carcinoma (SCC-9 and SCC-25) in vitro. The results indicated that zebularine significantly (P<0.05) reduced viability and DNA synthesis of treated cancer cells, by induction of cell cycle arrest at G2/M phase and apoptosis in both tested cell lines. This effect was confirmed to be mediated through p21/CHK1- and caspase 3/PARP-dependent pathways, respectively. However, no methylation was observed in the promoter region of the upregulated p21 and CHK1 genes. This may indicate that the alteration of p21 and CHK1 following zebularine administration was not due to inhibition of methylation of their promoter. Interestingly, it was observed that zebularine continued to influence cell viability for a week following its withdrawal. This may indicate feasibility of novel drug administration strategies, in which, daily administration of the drug replaced by weekly use, leading to improved therapeutic process and cost-effectiveness of the treatment in head and neck cancer.