Inhibition of Topoisomerase IIα and Induction of Apoptosis in Gastric Cancer Cells by 19-Triisopropyl Andrographolide.
Inhibition of Topoisomerase IIα and Induction of Apoptosis in Gastric Cancer Cells by 19-Triisopropyl Andrographolide.
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DOI：
10.22034/apjcp.2017.18.10.2845
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发表时间：
2017-10-26
期刊：
影响因子：
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通讯作者：
Chairoungdua A
中科院分区：
文献类型：
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作者：
Monger A;Boonmuen N;Suksen K;Saeeng R;Kasemsuk T;Piyachaturawat P;Saengsawang W;Chairoungdua A
胃癌是东亚最常见的癌症。增加的化疗耐药性和全身毒性使目前的化疗复杂化，导致迫切需要更有效的药物。本研究报告了穿心莲内酯类似物（19-三异丙基穿心莲内酯，类似物-6）在胃癌细胞、MKN-45和AGS细胞中的有效DNA拓扑异构酶IIα抑制活性。该类似物对两种胃癌细胞系均具有强效细胞毒性，48 h时MKN-45和AGS细胞的半数最大抑制浓度（IC 50值）分别为6.3±0.7 μM和1.7±0.05 μM。它比母体穿心莲内酯和临床上使用的依托泊苷更有效，其中穿心莲内酯在MKN-45中的IC_（50）值>50 μM，在AGS细胞中的IC_（50）值为11.3±2.9 μM，依托泊苷在MKN-45中的IC_（50）值为28.5±4.4 μM，在AGS细胞中的IC_（50）值为4.08±0.5 μM。2 μM浓度的Anglycerol-6显著抑制AGS细胞中的DNA拓扑异构酶IIα酶，诱导DNA损伤，激活切割的PARP-1和Caspase 3，导致晚期细胞凋亡。有趣的是，肿瘤抑制基因p53的表达没有被激活。这些结果表明，19-三异丙基-穿心莲内酯在其对拓扑异构酶IIα酶的主要靶点的新兴选择性，通过p53非依赖性机制诱导DNA损伤和凋亡方面的重要性。因此，这些结果提供了19-三异丙基穿心莲内酯作为胃癌抗癌剂的潜力的见解。穿心莲内酯的化学转化是从具有生物活性的天然产物中发现一类新型抗癌药物的一种很有前途的策略。
Gastric cancer is the most common cancer in Eastern Asia. Increasing chemoresistance and general systemic toxicities have complicated the current chemotherapy leading to an urgent need of more effective agents. The present study reported a potent DNA topoisomerase IIα inhibitory activity of an andrographolide analogue (19-triisopropyl andrographolide, analogue-6) in gastric cancer cells; MKN-45, and AGS cells. The analogue was potently cytotoxic to both gastric cancer cell lines with the half maximal inhibitory concentration (IC50 values) of 6.3±0.7 μM, and 1.7±0.05 μM at 48 h for MKN-45, and AGS cells, respectively. It was more potent than the parent andrographolide and the clinically used, etoposide with the IC50 values of >50 μM in MKN-45 and 11.3±2.9 μM in AGS cells for andrographolide and 28.5±4.4 μM in MKN-45 and 4.08±0.5 μM in AGS cells for etoposide. Analogue-6 at 2 μM significantly inhibited DNA topoisomerase IIα enzyme in AGS cells, induced DNA damage, activated cleaved PARP-1, and Caspase3 leading to late cellular apoptosis. Interestingly, the expression of tumor suppressor p53 was not activated. These results show the importance of 19-triisopropyl-andrographolide in its emerging selectivity to primary target on topoisomerase IIα enzyme, inducing DNA damage and apoptosis by p53- independent mechanism. Thereby, the results provide insights of the potential of 19-triisopropyl andrographolide as an anticancer agent for gastric cancer. The chemical transformation of andrographolide is a promising strategy in drug discovery of a novel class of anticancer drugs from bioactive natural products.