Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy.
Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy.
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DOI：
10.1371/journal.pone.0106485
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Vasko MR
中科院分区：
文献类型：
--
作者：
Kelley MR;Jiang Y;Guo C;Reed A;Meng H;Vasko MR
虽然化疗引起的周围神经病变（CIPN）是铂类药物的剂量限制性副作用，但这种毒性的机制仍不清楚。我们实验室以前的工作表明，顺铂诱导的CIPN是继发于DNA损伤的，DNA损伤易受碱基切除修复（BER）的影响。为了进一步检验这一假设，我们研究了顺铂，奥沙利铂和卡铂对细胞存活，DNA损伤，ROS产生和功能终点在培养的大鼠感觉神经元中的BER蛋白AP核酸内切酶/氧化还原因子-1（APE 1）的表达减少的存在或不存在的影响。使用肽能感觉神经元功能的原位模型，我们研究了铂类药物对后肢辣椒素诱发的血管舒张的影响。将培养物中的感觉神经元暴露于三种铂类药物会导致细胞凋亡和细胞死亡的浓度依赖性增加，尽管卡铂的浓度比顺铂高10倍。如先前用顺铂观察到的，奥沙利铂和卡铂也增加DNA损伤，如磷酸-H2 AX增加所示，并减少辣椒素诱发的CGRP从神经元培养物中的释放。顺铂和奥沙利铂都增加了ROS的产生以及8-氧代鸟嘌呤DNA加合物水平，而卡铂没有。降低神经元培养物中APE 1的水平增强顺铂和奥沙利铂诱导的毒性，但不改变卡铂的作用。使用体内模型，全身注射顺铂（3 mg/kg）、奥沙利铂（3 mg/kg）或卡铂（30 mg/kg），每周一次，持续三周，导致辣椒素诱发的血管舒张减少，其发作延迟。顺铂对辣椒素引起的血管舒张的影响被衰减的E3330，APE 1的氧化还原抑制剂，偶然增强APE 1 DNA修复活性的感觉神经元的长期管理。这些结果支持BER途径，特别是APE 1在顺铂和奥沙利铂引起的感觉神经病变中的重要性，而不是卡铂，并表明增强DNA修复可能是CIPN的治疗靶点。
Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE1, in sensory neuropathy caused by cisplatin and oxaliplatin, but not carboplatin and suggest that augmenting DNA repair could be a therapeutic target for CIPN.
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影响因子：
6.6
作者：
Bapat A;Fishel ML;Kelley MR
通讯作者：
Kelley MR
影响因子：
45.3
作者：
GREGG, RW;MOLEPO, JM;STEWART, DJ
通讯作者：
STEWART, DJ
影响因子：
5.3
作者：
Dzagnidze, Anna;Katsarava, Zaza;Thomale, Juergen
通讯作者：
Thomale, Juergen
DOI：
10.1016/b978-0-12-384999-1.10013-7
发表时间：
2012-01-01
期刊：
DNA REPAIR IN CANCER THERAPY: MOLECULAR TARGETS AND CLINICAL APPLICATIONS
影响因子：
--
作者：
Duarte, Djane Braz;Vasko, Michael R.
通讯作者：
Vasko, Michael R.
影响因子：
3.3
作者：
El-Khamisy, S. F.;Caldecott, K. W.
通讯作者：
Caldecott, K. W.