Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants.
Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants.
复制标题
DOI：
10.1038/cddis.2013.172
复制
发表时间：
2013-06-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
近年来，植物性膳食抗氧化剂因其在动物模型中的化学预防和癌症治疗能力而引起了人们的极大兴趣。百里醌（Thymoquinone， TQ）是黑草挥发油的主要生物活性成分，具有抗炎、心血管、镇痛、抗肿瘤、抗癌和化学预防等药理作用。虽然已经提出了几种TQ的化学预防和抗癌作用机制，但尚未阐明TQ的明确作用机制。TQ是一种已知的低浓度抗氧化剂，大多数阐明其机制的研究都集中在抗氧化性能上。然而，最近的出版物表明，高浓度的TQ可能起到促氧化剂的作用。众所周知，即使在铜等过渡金属离子存在的低浓度情况下，植物来源的抗氧化剂也能转化为促氧化剂。在各种恶性肿瘤中，组织、细胞和血清铜水平均显著升高。铜是存在于染色质中的一种重要的金属离子，与DNA碱基，特别是鸟嘌呤密切相关。利用人类外周淋巴细胞和彗星试验，我们首次发现TQ能够引起氧化细胞DNA断裂。这种DNA断裂可以被铜螯合剂、新根碱和根根碱以及活性氧清除剂所抑制。此外，发现TQ靶向前列腺癌细胞系中的细胞铜，导致促氧化性细胞死亡。我们认为这种促氧化细胞毒性机制更好地解释了植物源抗氧化剂的抗癌活性。
Plant-derived dietary antioxidants have attracted considerable interest in recent past for their chemopreventive and cancer therapeutic abilities in animal models. Thymoquinone (TQ) is the major bioactive constituent of volatile oil of Nigella sativa and has been shown to exert various pharmacological properties, such as anti-inflammatory, cardiovascular, analgesic, anti-neoplastic, anticancer and chemopreventive. Although several mechanisms have been suggested for the chemopreventive and anticancer activity of TQ, a clear mechanism of action of TQ has not been elucidated. TQ is a known antioxidant at lower concentrations and most of the studies elucidating the mechanism have centered on the antioxidant property. However, recent publications have shown that TQ may act as a prooxidant at higher concentrations. It is well known that plant-derived antioxidants can switch to prooxidants even at low concentrations in the presence of transition metal ions such as copper. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Copper is an important metal ion present in the chromatin and is closely associated with DNA bases, particularly guanine. Using human peripheral lymphocytes and comet assay, we first show that TQ is able to cause oxidative cellular DNA breakage. Such a DNA breakage can be inhibited by copper-chelating agents, neocuproine and bathocuproine, and scavengers of reactive oxygen species. Further, it is seen that TQ targets cellular copper in prostate cancer cell lines leading to a prooxidant cell death. We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants.
登录
查看更多内容
影响因子：
3.8
作者：
Bhat, S. H.;Azmi, A. S.;Hadi, S. M.
通讯作者：
Hadi, S. M.
影响因子：
6.4
作者：
El-Mahdy, MA;Zhu, QZ;Wani, AA
通讯作者：
Wani, AA
DOI：
10.1016/0165-1161(94)90031-0
发表时间：
1994-08-01
期刊：
MUTATION RESEARCH-ENVIRONMENTAL MUTAGENESIS AND RELATED SUBJECTS
影响因子：
--
作者：
BHAT, R;HADI, SM
通讯作者：
HADI, SM
影响因子：
2.7
作者：
AHMED, MS;RAMESH, V;HADI, SM
通讯作者：
HADI, SM
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel