Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage.
Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage.
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DOI：
10.3390/molecules21121758
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发表时间：
2016-12-21
期刊：
影响因子：
--
通讯作者：
Katiyar SK
中科院分区：
文献类型：
--
作者：
Pal HC;Katiyar SK
拓扑异构酶已被证明在癌症进展中起作用。在这里，我们研究了cryptolepine，一种植物生物碱，对人非黑色素瘤皮肤癌细胞（NMSCC）的生长和潜在的作用机制的影响。为此，SCC-13和A431细胞系用作体外模型。我们的研究表明，SCC-13和A431细胞表达更高的水平，以及活性的拓扑异构酶（拓扑异构酶I和拓扑异构酶II）与正常人表皮角质形成细胞相比。用Cryptolepine（2.5、5.0和7.5 µM）处理NMSCC 24 h导致拓扑异构酶活性显著降低，这与彗星试验检测到的大量DNA损伤相关。Cryptolepine诱导的DNA损伤导致：（i）ATM/ATR、BRCA 1、Chk 1/Chk 2和γ H2 AX的磷酸化增加;（ii）p53信号级联的激活，包括p16和p21的蛋白表达增强;（iii）细胞周期蛋白依赖性激酶、细胞周期蛋白D1、细胞周期蛋白A、细胞周期蛋白E和参与细胞分裂的蛋白（例如，Cdc 25 a和Cdc 25 b）导致细胞周期停滞在S期;和（iv）线粒体膜电位被破坏，细胞色素c释放。Cryptolepine引起的NMSCC的这些变化导致细胞活力、集落形成的显著降低和凋亡性细胞死亡的增加。
Topoisomerases have been shown to have roles in cancer progression. Here, we have examined the effect of cryptolepine, a plant alkaloid, on the growth of human non-melanoma skin cancer cells (NMSCC) and underlying mechanism of action. For this purpose SCC-13 and A431 cell lines were used as an in vitro model. Our study reveals that SCC-13 and A431 cells express higher levels as well as activity of topoisomerase (Topo I and Topo II) compared with normal human epidermal keratinocytes. Treatment of NMSCC with cryptolepine (2.5, 5.0 and 7.5 µM) for 24 h resulted in marked decrease in topoisomerase activity, which was associated with substantial DNA damage as detected by the comet assay. Cryptolepine induced DNA damage resulted in: (i) an increase in the phosphorylation of ATM/ATR, BRCA1, Chk1/Chk2 and γH2AX; (ii) activation of p53 signaling cascade, including enhanced protein expressions of p16 and p21; (iii) downregulation of cyclin-dependent kinases, cyclin D1, cyclin A, cyclin E and proteins involved in cell division (e.g., Cdc25a and Cdc25b) leading to cell cycle arrest at S-phase; and (iv) mitochondrial membrane potential was disrupted and cytochrome c released. These changes in NMSCC by cryptolepine resulted in significant reduction in cell viability, colony formation and increase in apoptotic cell death.
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DOI：
10.1038/nrc2607
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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DOI：
10.1111/j.1432-1033.1997.t01-2-00527.x
发表时间：
1997-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
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作者：
Meijer, L;Borgne, A;Moulinoux, JP
通讯作者：
Moulinoux, JP
影响因子：
4.3
作者：
Gogvadze, Vladimir;Orrenius, Sten;Zhivotovsky, Boris
通讯作者：
Zhivotovsky, Boris
影响因子：
8
作者：
He, GG;Siddik, ZH;Kuang, J
通讯作者：
Kuang, J
DOI：
10.1038/nrc2608
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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