Abstract：
Cervical cancer cells possess high levels of reactive oxygen species (ROS); thus, increasing oxidative stress above the toxicity threshold to induce cell death is a promising chemotherapeutic strategy. However, the underlying mechanisms of cell death are elusive, and efficacy and toxicity issues remain. Within DNA, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent base lesion repaired by 8-oxoguanine glycosylase 1 (OGG1)-initiated base excision repair. Cancer cells also express high levels of MutT homolog 1 (MTH1), which prevents DNA replication-induced incorporation of 8-oxoG into the genome by hydrolyzing 8-oxo-7,8-dihydro-2\'-deoxyguanosine 5\'-triphosphate (8-oxo-dGTP). Here, we revealed that ROS-inducing agents triggered cervical cancer to undergo parthanatos, which was mainly induced by massive DNA strand breaks resulting from overwhelming 8-oxoG excision by OGG1. Furthermore, the MTH1 inhibitor synergized with a relatively low dose of ROS-inducing agents by enhancing 8-oxoG loading in the DNA. In vivo, this drug combination suppressed the growth of tumor xenografts, and this inhibitory effect was significantly decreased in the absence of OGG1. Hence, the present study highlights the roles of base repair enzymes in cell death induction and suggests that the combination of lower doses of ROS-inducing agents with MTH1 inhibitors may be a more selective and safer strategy for cervical cancer chemotherapy.
摘要：
宫颈癌细胞具有高水平的活性氧（ROS）；因此，增加氧化应激高于毒性阈值以诱导细胞死亡是一种有前途的化疗策略。然而,细胞死亡的潜在机制难以捉摸，功效和毒性问题依然存在。在DNA中，8-氧代-7,8-二氢鸟嘌呤（8-oxoG）是由8-氧代鸟嘌呤糖基化酶1（OGG1）启动的碱基切除修复修复修复的最常见的碱基病变。癌细胞也表达高水平的MutT同源物1（MTH1），通过水解8-氧代-7,8-二氢-2'-脱氧鸟苷5'-三磷酸（8-氧代-dGTP）来防止DNA复制诱导的8-氧代G掺入基因组。这里,我们揭示了ROS诱导剂引发宫颈癌经历parthanatos,这主要是由OGG1压倒性的8-oxoG切除导致的大量DNA链断裂引起的。此外，MTH1抑制剂通过增强DNA中的8-oxoG负载与相对低剂量的ROS诱导剂协同作用。在体内,这种药物组合抑制了肿瘤异种移植物的生长，在不存在OGG1的情况下，这种抑制作用显着降低。因此，本研究强调了碱基修复酶在细胞死亡诱导中的作用,并提示较低剂量的ROS诱导剂与MTH1抑制剂的组合可能是宫颈癌化疗的更有选择性和更安全的策略.
