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蜡菊黄素诱导DNA损伤，触发Ca Ski细胞中JNK介导的凋亡。

Helichrysetin Induces DNA Damage that Triggers JNK-Mediated Apoptosis in Ca Ski Cells.

作者信息

Fong Ho Yen, Abd Malek Sri Nurestri, Yee Hui Shin, Karsani Saiful Anuar

机构信息

Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.

出版信息

Pharmacogn Mag. 2017 Oct-Dec;13(52):607-612. doi: 10.4103/pm.pm_53_17. Epub 2017 Nov 13.

DOI:10.4103/pm.pm_53_17
PMID:29200721
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5701399/
Abstract

BACKGROUND

Cervical cancer has become one of the most common cancers in women and currently available treatment options for cervical cancer are very limited. Naturally occurring chalcones and its derivatives have been studied extensively as a potential anticancer agent in different types of cancer and helichrysetin is naturally occurring chalcone that possess potent antiproliferative activity toward human cancer cells.

MATERIALS AND METHODS

Inhibitory activity of helichrysetin was evaluated at different concentrations. Ability of helichrysetin to induce apoptosis and its relation with c-Jun N-terminal kinase (JNK)-mediated mechanism of apoptosis was assessed using flow cytometry and Western blotting.

RESULTS

Helichrysetin inhibited Ca Ski cells at half maximal inhibitory concentration 30.62 ± 0.38 μM. This compound has the ability to induce DNA damage, mitochondrial membrane disruption, and loss of cell membrane integrity. We have shown that apoptosis was induced through the activation of JNK-mediated apoptosis by DNA damage in the cells then triggering p53-downstream apoptotic pathway with increased expression of pro-apoptotic proteins, Bax and caspase 3, and suppression of Bcl-2 anti-apoptotic protein. DNA damage in the cells also caused phosphorylation of protein ataxia-telangiectasia mutated, an activator of DNA damage response.

CONCLUSION

We conclude that helichrysetin can inhibit Ca Ski cells through DNA damage-induced JNK-mediated apoptotic pathway highlighting the potential of this compound as anticancer agent for cervical cancer.

SUMMARY

Helichrysetin induced DNA damage in Ca Ski cellsDNA damage caused JNK-mediated phosphorylation of p53 resulting in p53-mediated apoptosisHelichrysetin is a potential DNA damage inducing agent through JNK activation to kill human cervical carcinoma cells. ATM: Ataxia-telangiectasia mutated, DAPI: 4',6-diamidino-2-phenylindole, DMSO: Dimethyl sulfoxide, FITC: Fluorescein isothiocyanate, IC: Half maximal inhibitory concentration, JC1-5,5',6,6'-Tetrachloro: 1',3,3'-tetraethylbenzimidazolylcarbocyanine, iodide, JNK: c-Jun N-terminal kinase, MMP: Mitochondrial membrane potential, PBS: Phosphate-buffered saline, SRB: Sulforhodamine B, TUNEL: Terminal deoxynucleotidyl transferase dUTP nick labeling.

摘要

背景

宫颈癌已成为女性最常见的癌症之一，目前宫颈癌的可用治疗选择非常有限。天然存在的查尔酮及其衍生物作为一种潜在的抗癌剂已在不同类型的癌症中得到广泛研究，而蜡菊黄酮是一种天然存在的查尔酮，对人类癌细胞具有强大的抗增殖活性。

材料与方法

评估了不同浓度下蜡菊黄酮的抑制活性。使用流式细胞术和蛋白质印迹法评估蜡菊黄酮诱导细胞凋亡的能力及其与c-Jun氨基末端激酶（JNK）介导的凋亡机制的关系。

结果

蜡菊黄酮在半最大抑制浓度30.62±0.38μM时抑制Ca Ski细胞。该化合物具有诱导DNA损伤、线粒体膜破坏和细胞膜完整性丧失的能力。我们已经表明，细胞凋亡是通过细胞中DNA损伤激活JNK介导的凋亡，然后触发p53下游凋亡途径，增加促凋亡蛋白Bax和半胱天冬酶3的表达，并抑制抗凋亡蛋白Bcl-2来诱导的。细胞中的DNA损伤还导致共济失调毛细血管扩张突变蛋白（一种DNA损伤反应激活剂）的磷酸化。

结论

我们得出结论，蜡菊黄酮可通过DNA损伤诱导的JNK介导凋亡途径抑制Ca Ski细胞，突出了该化合物作为宫颈癌抗癌剂的潜力。

总结

蜡菊黄酮在Ca Ski细胞中诱导DNA损伤

DNA损伤导致JNK介导的p53磷酸化，从而导致p53介导的细胞凋亡

蜡菊黄酮是一种通过JNK激活诱导DNA损伤以杀死人宫颈癌细胞的潜在药物。ATM：共济失调毛细血管扩张突变蛋白，DAPI：4',6-二脒基-2-苯基吲哚，DMSO：二甲基亚砜，FITC：异硫氰酸荧光素，IC：半最大抑制浓度，JC1-5,5',6,6'-四氯：1',3,3'-四乙基苯并咪唑基碳菁碘化物，JNK：c-Jun氨基末端激酶，MMP：线粒体膜电位，PBS：磷酸盐缓冲盐水，SRB：磺酰罗丹明B，TUNEL：末端脱氧核苷酸转移酶dUTP缺口末端标记

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