Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
Mutagenesis. 2013 May;28(3):257-61. doi: 10.1093/mutage/ges079. Epub 2013 Jan 29.
The intention of the current study was to investigate the effect of non-toxic doses of dihydrokainate on the capacity of repair of DNA damage and apoptosis induced by doxorubicin in mouse bone-marrow cells. The scoring of micronuclei and olive tail moment was undertaken in the current study as markers of DNA damage and repair. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak. Oxidative stress markers such as bone-marrow reactive oxygen species, lipid peroxidation, reduced and oxidised glutathione were assessed as a possible mechanism underlying this amelioration. In addition, the influence of dihydrokainate on doxorubicin-induced topoisomerase II inhibition was examined. Dihydrokainate was neither genotoxic nor apoptogenic at doses equivalent to 10 or 20mg/kg/day for 7 days. Pre-treatment of mice with dihydrokainate significantly enhances the repair of doxorubicin-induced DNA damage and reduced doxorubicin-induced apoptosis depending on dose. Doxorubicin induced marked biochemical alterations characteristic of oxidative stress, including increased reactive oxygen species, enhanced lipid peroxidation and reduction in the reduced/oxidised glutathione ratio. Prior administration of dihydrokainate ahead of doxorubicin challenge ameliorated these oxidative stress markers. Importantly, dihydrokainate treatment had no antagonising effect on doxorubicin-induced topoisomerase II inhibition. Conclusively, this study provides for the first time that dihydrokainate enhances the repair of doxorubicin-induced DNA damage, which resides, at least in part, in its ability to modulate the cellular antioxidant levels. Based on our data presented, strategies can be developed to enhance the repair of doxorubicin-induced genomic damage in normal cells using dihydrokainate without diminishing doxorubicin's anti-topoisomerase II activity. Thus, improvement of doxorubicin's therapeutic index may be achieved by using dihydrokainate.
本研究旨在探讨无毒剂量的二氢卡因对阿霉素诱导的小鼠骨髓细胞 DNA 损伤修复和细胞凋亡的影响。目前的研究采用微核评分和橄榄尾矩作为 DNA 损伤和修复的标志物。通过出现亚二倍体 DNA 峰来分析细胞凋亡。作为这种改善的可能机制，评估了骨髓活性氧、脂质过氧化、还原型和氧化型谷胱甘肽等氧化应激标志物。此外，还研究了二氢卡因对阿霉素诱导的拓扑异构酶 II 抑制的影响。二氢卡因在相当于 10 或 20mg/kg/天连续 7 天的剂量下既没有遗传毒性也没有促凋亡作用。用二氢卡因预处理小鼠可显著增强阿霉素诱导的 DNA 损伤修复，并根据剂量减少阿霉素诱导的细胞凋亡。阿霉素诱导了明显的氧化应激特征的生化改变，包括活性氧增加、脂质过氧化增强和还原型/氧化型谷胱甘肽比值降低。在阿霉素攻击前给予二氢卡因可改善这些氧化应激标志物。重要的是，二氢卡因处理对阿霉素诱导的拓扑异构酶 II 抑制没有拮抗作用。总之，本研究首次表明，二氢卡因增强了阿霉素诱导的 DNA 损伤的修复，至少部分原因在于其调节细胞抗氧化水平的能力。基于我们目前的数据，可开发使用二氢卡因增强正常细胞中阿霉素诱导的基因组损伤修复的策略，而不会降低阿霉素的抗拓扑异构酶 II 活性。因此，使用二氢卡因可能会提高阿霉素的治疗指数。
