Napso Tina, Fares Fuad
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mount Carmel, 31905 Haifa, Israel.
Int J Oncol. 2014 Jun;44(6):1971-9. doi: 10.3892/ijo.2014.2386. Epub 2014 Apr 11.
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.
泽布勒林是一种有效的DNA甲基转移酶抑制剂，有可能影响基因调控，从而改变细胞行为。本研究阐述了泽布勒林在体外对人鳞状细胞癌（SCC - 9和SCC - 25）的作用。结果表明，泽布勒林通过诱导受试癌细胞在G2/M期细胞周期停滞和凋亡，显著（P<0.05）降低了处理后癌细胞的活力和DNA合成。这一作用分别通过p21/CHK1依赖性途径和caspase 3/PARP依赖性途径介导。然而，在p21和CHK1基因上调的启动子区域未观察到甲基化。这可能表明给药后p21和CHK1的改变并非由于其启动子甲基化受到抑制。有趣的是，观察到泽布勒林停药后仍能持续影响细胞活力一周。这可能表明新型给药策略具有可行性，即每日给药可被每周用药取代，从而改善头颈部癌的治疗过程和治疗的成本效益。
