Department of Biological Science and Technology and Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan.
Eur J Pharmacol. 2010 Apr 25;632(1-3):23-32. doi: 10.1016/j.ejphar.2010.01.009. Epub 2010 Jan 25.
Lung cancer is the leading cause of death among cancers worldwide and non-small cell lung cancer (NSCLC) comprises more than 80% of lung cancer cases. Treatment options for patients with advanced NSCLC have evolved in the last decade with the advent of novel biological agents. Andrographolide, a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to have the potential to be developed as a chemotherapeutic agent. In order to understand the anti-cancer properties of andrographolide, we examined its effect on migration and invasion in human NSCLC A549 cells. The results of wound-healing assay and in vitro transwell assay revealed that andrographolide inhibited dose-dependently the migration and invasion of A549 cells under non-cytotoxic concentrations. Molecular data showed that the effect of andrographolide in A549 cells might be mediated via sustained inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt signal involved in the up-regulation of matrix metalloproteinases (MMPs). Our results showed that andrographolide exerted an inhibitory effect on the activity and the mRNA and protein levels of MMP-7, but not MMP-2 or MMP-9. The andrographolide-inhibited MMP-7 expression or activity appeared to occur via activator protein-1 (AP-1) because of its DNA binding activity was suppressed by andrographolide. Additionally, the transfection of Akt over-expression vector (Akt1 cDNA) to A549 cells could result in an increase expression of MMP-7 concomitantly with a marked induction on cell invasion. These findings suggested that the inhibition on MMP-7 expression by andrographolide may be through suppression on PI3K/Akt/AP-1 signaling pathway, which in turn led to the reduced invasiveness of the cancer cells.
肺癌是全球癌症死亡的主要原因，而非小细胞肺癌（NSCLC）占肺癌病例的 80%以上。在过去的十年中，随着新型生物制剂的出现，晚期 NSCLC 患者的治疗选择已经发生了变化。穿心莲内酯是一种从传统草药穿心莲中分离出来的二萜内酯，已知具有开发成为化疗药物的潜力。为了了解穿心莲内酯的抗癌特性，我们研究了它对人非小细胞肺癌 A549 细胞迁移和侵袭的影响。伤口愈合试验和体外 Transwell 试验的结果表明，穿心莲内酯在非细胞毒性浓度下剂量依赖性地抑制 A549 细胞的迁移和侵袭。分子数据表明，穿心莲内酯在 A549 细胞中的作用可能是通过持续失活参与基质金属蛋白酶（MMPs）上调的磷脂酰肌醇 3-激酶（PI3K）/Akt 信号来介导的。我们的结果表明，穿心莲内酯对 MMP-7 的活性以及 mRNA 和蛋白水平均具有抑制作用，但对 MMP-2 或 MMP-9 没有作用。穿心莲内酯抑制 MMP-7 表达或活性似乎是通过激活蛋白-1（AP-1）发生的，因为穿心莲内酯抑制了其 DNA 结合活性。此外，将 Akt 过表达载体（Akt1 cDNA）转染至 A549 细胞中，可导致 MMP-7 的表达增加，同时细胞侵袭明显增加。这些发现表明，穿心莲内酯对 MMP-7 表达的抑制可能是通过抑制 PI3K/Akt/AP-1 信号通路，从而降低癌细胞的侵袭性。
