反复药物暴露致错配修复功能障碍使人类神经胶质瘤细胞获得替莫唑胺耐药性。
Human Glioma Cells Acquire Temozolomide Resistance After Repeated Drug Exposure DNA Mismatch Repair Dysfunction.
机构信息
Department of Neurosurgery, Fujita Health University, Toyoake, Japan.
Department of Neurosurgery, Fujita Health University, Toyoake, Japan
出版信息
Anticancer Res. 2020 Mar;40(3):1315-1323. doi: 10.21873/anticanres.14073.
BACKGROUND/AIM: Temozolomide (TMZ) induces prolonged arrest of human glioma cells in the G/M phase and inhibition of the G checkpoint intensifies the effect of TMZ. These findings suggest that the G checkpoint is linked to DNA repair mechanisms.
MATERIALS AND METHODS
To clarify the mechanism of TMZ resistance, we established TMZ-resistant (TR) clones by serial treatment of U87MG cells with TMZ. We evaluated TMZ-induced cell cycle arrest and the effect of various G checkpoint inhibitors.
RESULTS
We observed that longer exposure (over 6 months) to TMZ enriched the proportion of TR clones that underwent only minimal G arrest following TMZ treatment compared to short exposure (4 months) to TMZ. Expression of MSH6 was reduced in these clones. None of the G checkpoint inhibitors could resensitize TR clones to TMZ.
CONCLUSION
Longer drug treatment may induce resistance of cells to DNA damaging agent(s) by means of mismatch repair modification.
背景/目的：替莫唑胺（TMZ）可诱导人胶质瘤细胞在 G2/M 期长时间阻滞，并抑制 G 期检查点，从而增强 TMZ 的作用。这些发现表明 G 期检查点与 DNA 修复机制有关。
材料和方法
为了阐明 TMZ 耐药的机制，我们通过对 U87MG 细胞进行 TMZ 序贯处理，建立了 TMZ 耐药（TR）克隆。我们评估了 TMZ 诱导的细胞周期阻滞和各种 G 期检查点抑制剂的作用。
结果
我们观察到，与短时间（4 个月）暴露于 TMZ 相比，长时间（超过 6 个月）暴露于 TMZ 可使 TR 克隆在 TMZ 处理后仅经历最小程度的 G 期阻滞，比例增加。这些克隆中 MSH6 的表达减少。没有一种 G 期检查点抑制剂能使 TR 克隆对 TMZ 重新敏感。
结论
较长时间的药物治疗可能通过错配修复修饰诱导细胞对 DNA 损伤剂的耐药性。
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