Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-β1

Abstract

Abstract. In this study we investigated the potential effects of Angelica sinensis on the growth and metastasis in human lung adenocarcinoma A549 cells. In vitro the Cck-8 assays showed that Angelica sinensis had weak antiproliferative effect on A549 cells only at high concentration. The cell adhesion assay showed that Angelica sinensis decreased the adhesive ability of A549 cells in a dose-and time-dependent manner. Transwell invasion and migration assay showed that Angelica sinensis reduced the invasive and migratory abilities of A549 cells in a dose-dependent manner. In vivo the animal experiments showed that Angelica sinensis suppressed lung metastasis of nude mice at high concentration. Then, we attempted to clarify the mechanisms of anti-metastatic activities of Angelica sinensis. The results showed Angelica sinensis inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), it involved the down-regulation of the expressions of MMP-2 and MMP-9 at both the protein and mRNA levels, which may be associated with Angelica sinensis suppressing the expression of TGF-β1. It also involved the increase of the tissue inhibitors of metalloproteinases TIMP-2, but TIMP-1 decreased upon incubation of A549 cells with Angelica sinensis. The results suggest that Angelica sinensis might exert anti-growth and anti-metastasis activity against lung cancer cells through the decrease of MMP-2, MMP-9, TGF-β1 and TIMP-1 and increase of TIMP-2. IntroductionNon-small cell lung carcinoma (NSCLC) is currently one of the leading causes of death in China, its high mortality is attributed to early metastasis. About 70-90% patients with lung cancer need radiation therapy, and therefore, radiation lung injury is the most common complication (1). It limits the increasing of radiation dose and influences the life quality of patients or even threatens their life. Many traditional Chinese medicines have great efficacy in radiation lung injury. The root of Angelica sinensis, also known as 'Danggui' was a popular herbal medicine and widely used for many diseases in China. It has been used for more than 10 years in our hospital to treat lung fibrosis and shows good curative effect in radiation pulmonary fibrosis (2-4).Angelica sinensis belongs to 'activating blood and dissolving stasis' kind of traditional Chinese medicine, and some researchers think this kind of medicine can promote tumor metastasis. Li et al first reported Salvia miltiorrhiza Bunge and Radix Paeoniae Rubra such as 'activating blood and dissolving stasis' traditional Chinese medicine can promote tumor metastasis, we pay high attention to it (5). Han et al found the metastasis rate of nasopharyngeal carcinoma increased to 2.67 times compare with the control after using 'activating blood and dissolving stasis' kind of traditional Chinese medicine (6). But also, there is research with the opposite conclusion (7). Therefore, the use of Angelica sinensis needs to be clarified to confirm whether it promotes or inhibits metastasis of l...

An Experimental Novel Study:Angelica sinensisPrevents Epidural Fibrosis in Laminectomy Rats via Downregulation of Hydroxyproline, IL-6, and TGF-β1

“…All of the above support our theory of A. sinensis 's antifibrotic, anti-inflammatory, and antiproliferative roles. In addition, and literatures within the medical community also support our theory by reporting on A. sinensis 's anti-fibrotic, anti-inflammatory, and antiproliferative properties [24, 25, 30]. Pharmacological studies have shown that A. sinensis extracts are able to improve local and systemic blood flow, which provides benefits in patients with ulcer, cancer, and other diseases.…”

“…Recent studies also mention that A. sinensis has the ability to suppress the expression of TGF- β 1 in lung cancer study [24] and the expressions of TNF- α and IL-6 in chronic inflammatory diseases [25]. These studies inspired us to determine whether A. sinensis plays a similar role with TGF- β 1 and IL-6 in EF rats.…”

Phthalide Derivatives from Angelica Sinensis Decrease Hemoglobin Oxygen Affinity: A New Allosteric-Modulating Mechanism and Potential Use as 2,3-BPG Functional Substitutes

“…Its neuroprotective 4 and anti-cancer 5–8 effects have also been documented. It is of profound significance to note that these above-mentioned syndromes/diseases are commonly linked with the malfunction of Hb oxygen transport and thus cellular hypoxia to varying extents (see Supplementary Information).…”

“…Its anti-cardiovascular 3 , neuroprotective 4 , and anti-cancer 5–8 effects have also been reported. Previous compositional analysis of AS have identified phthalide derivatives, ferulic acid and polysaccharides as the major constituents of AS, though their relative abundance may vary depending on the area and growth conditions 9–12 .…”

Polypeptide N-acetylgalactosaminyltransferase 2 regulates cellular metastasis-associated behavior in gastric cancer

“…Proteins of the MMP family are involved in the breakdown of ECM in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis (29). Among the many MMPs that have been identified, MMP-2 encodes an enzyme which degrades type IV collagen, the major structural component of basement membranes.…”