Flavanone and 2'-OH flavanone inhibit metastasis of lung cancer cells via down-regulation of proteinases activities and MAPK pathway

Flavanones richly exist in citrus and have been well characterized to have various bioactive properties. However, the anti-metastasis properties of flavanones remain unclear. The anti-metastatic effects of six flavanones including flavanone, 2'-OH flavanone, 4'-OH flavanone, 6-OH flavanone, naringin, and naringenin were investigated in lung cancer cells. Despite little influence on cell viability, flavanone and 2'-OH flavanone markedly inhibited the invasion, motility, and cell-matrix adhesion of A549 cells. This was associated with a reduced expression of matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA) in treated cells. Treatment with flavanone and 2'-OH flavanone also potently attenuated the phosphorylations of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38(MAPK), as well as the activations of NF-kappaB and AP-1. The reduced expressions of MMP-2 and u-PA, as well as inhibition of cell invasion were obtained in the cultures treated with U0126 (ERK 1/2 inhibitor) and SB203580 (p38(MAPK) inhibitor). Thus, the inhibitory effects of flavanone and 2'-OH flavanone on the expression of MMP-2 and u-PA may be at least partly through inactivation of ERK 1/2 and p38(MAPK) signaling pathways. Finally, oral administration of flavanone and 2'-OH flavanone were evidenced by its inhibition on the metastasis of A549 cells and Lewis lung carcinoma (LLC) cells in vivo. In conclusion, flavanone and 2'-OH flavanone perturb the invasion and metastasis of lung cancer cells, thereby constituting an adjuvant treatment for metastasis control.     

过表达胃泌素促进胃癌细胞的增殖、迁移和侵袭

胃癌患者转移淋巴结中胃泌素基因的表达量是原发胃癌组织的42倍,推测胃泌素可能与胃癌转移密切相关. 本文通过构建含胃泌素基因的真核表达载体,成功获得过表达胃泌素的稳转胃癌细胞株AGS和SGC-7901, 并用MTT、细胞伤愈实验、Transwell 小室实验及ELISA检测过表达胃泌素对细胞迁移、侵袭及转移相关蛋白基质金属蛋白酶2（MMP-2）分泌能力的影响. 结果显示,过表达胃泌素稳转细胞的相对增殖率、 迁移入细胞致伤区的相对距离比对照组高,迁移和侵袭到Transwell下室面的细胞, 以及培养液中每mg蛋白质的MMP-2浓度也高于对照组的细胞. 结果提示,胃泌素通过促进胃癌细胞分泌MMP-2来增强细胞的迁移和侵袭能力. 该研究对揭示胃癌转移的分子机制具有重要意义.     

基质金属蛋白酶- 9, 组织抑制因子- 1 在进展期 胃癌中的表达与意义

目的：研究基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9）及其组织抑制因子-1（tissue inhibitor of metallopmteinase—1,TMP-1）在进展期胃癌中的表达情况,探讨二者的表达与胃癌侵袭转移闻的关系及二者间的联系。方法：应用免疫组化方法检测70例进展期胃癌标本中MMP-9,TIMP-1的表达,并进行回顾性随访。结果：馒反肌层以上者MMP-9的阳性表达（66．67％）明显高于肿瘤局限于粘膜、粘膜下者（20％P〈0.01）。MMP-9阳性表达与胃癌的淋巴转移与肝转移有相关性（P〈0．01）。TIMP-1的表达随胃癌浸润深度增加而减少,当肿瘤突破浆膜时TIMP-1的表达呈现陡降趋势（P〈0．01）。结论：MMP-9的过阳性表达和TIMP-1的表达失衡可能与胃癌转移行为有关。TIMP-1可能抑制胃癌的浸润转移。     

没食子酸对PI3K/AKT基因表达的影响及其对胃癌细胞的抗转移作用

为了调查在蔬菜中大量存在的酚酸(没食子酸(GA),咖啡酸(CA)和原儿茶酸(PCA))对胃腺癌(AGS)细胞转移的抑制作用,本研究在不同浓度的CA、PCA或GA中培养了AGS细胞24 h或48 h来检测AGS细胞活性对NF-κB、IκB、PI3K、AKT和小细胞GTPase表达和对细胞骨架F-肌动蛋白模式的影响。本研究发现,0.01 mmol/L GA诱导的细胞毒性与4.0 mmol/L PCA相同。GA对AGS细胞迁移有明显的抑制作用。AGS细胞的MMP-2/9表达被2.0μmol/L GA所抑制。GA对MMP-2/9的抑制作用有可能包括抑制NF-κB活性。多蛋白参与转移和细胞骨架重组信号通路,包括Ras、Cdc42、Rac1、RhoA、RhoB、PI3K和p38MAPK,也被GA所抑制。此外,细胞骨架F-肌动蛋白的免疫反应检测显示GA处理的显著抑制作用。本研究表明,GA有可能成为一种有效的预防和治疗胃癌转移的药物。     

Cholesterol inhibits MMP-9 expression in human epidermal keratinocytes and HaCaT cells

Cholesterol is a major component of skin lipids and acts as a regulator of vesicular trafficking and signal transduction. However, the function of cholesterol on matrix metalloproteinases (MMPs) expression of human skin is not fully understood. Here, we investigated the effects of cholesterol on MMP-9 expression in normal human keratinocytes (NHK) and HaCaT cells. Basal level of MMP-9 expression was decreased by cholesterol in NHK. On the other hand, MMP-9 expression was increased by the cholesterol depletion agent, methyl-beta-cyclodextrin (MbetaCD), while it was inhibited by cholesterol repletion in HaCaT cells. MbetaCD induced ERK and JNK phosphorylation were prevented by cholesterol repletion. The inhibition of ERK and JNK decreased MbetaCD-induced MMP-9 expression. Therefore, our results suggest that cholesterol regulates MMP-9 expression through ERK and JNK-dependent pathways.     

Human tumor cell growth inhibition by nontoxic anthocyanidins, the pigments in fruits and vegetables

Anthocyanidins, the aglycones of anthocyanins, impart brilliant colors in many fruits and vegetables. The widespread consumption of diets rich in anthocyanin and anthocyanidins prompted us to determine their inhibitory effects on human cancer cell proliferation. Five anthocyanidins, cyanidin (1), delphinidin (2), pelargonidin (3), petunidin (4) and malvidin (5), and four anthocyanins, cyanidin-3-glucoside, cyanidin-3-galactoside, delphinidin-3-galactoside and pelargonidin-3-galactoside were tested for cell proliferation inhibitory activity against human cancer cell lines, AGS (stomach), HCT-116 (colon), MCF-7 (breast), NCI H460 (lung), and SF-268 (Central Nervous System, CNS) at 12.5-200 microg/mL concentrations. The viability of cells after exposure to anthocyanins and anthocyanidins was determined by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colorimetric methods. The anthocyanins assayed did not inhibit cell proliferation of cell lines tested at 200 microg/mL. However, anthocyanidins showed cell proliferation inhibitory activity. Malvidin inhibited AGS, HCT-116, NCI-H460, MCF-7 and SF-268 cell growth by 69, 75.7, 67.7, 74.7 and 40.5%, respectively, at 200 microg/mL. Similarly, pelargonidin inhibited AGS, HCT-116, NCI H460, MCF-7 and SF-268 cell growth by 64, 63, 62, 63 and 34%, respectively, at 200 microg/mL. At 200 microg/mL, cyanidin, delphinidin and petunidin inhibited the breast cancer cell growth by 47, 66 and 53%, respectively. This is the first report of tumor cell proliferation inhibitory activity by anthocyanidins.     

Malonylated Anthocyanins from Bulbs of Red Onion,Allium cepa L.

Four cyanidin-based anthocyanins (1–4) were isolated from the red onion, Allium cepa L. Pigments 1 and 3 were identified as cyanidin 3-glucoside (Cy 3-Glc) and 3-malonylglucoside (Cy 3-MaGlc), respectively, by cochromatography with standard pigments. Anthocyanins 2 and 4 were respectively determined as cyanidin 3-laminaribioside (Cy 3-Lam) and 3-malonyllaminaribioside (Cy 3-MaLam), a new anthocyanin, mainly by NMR tech-niques. Malonylated anthocyanins 3 and 4 were found for the first time in red onions.     

Complex anthocyanins from Ipomoea congesta

Six acylated anthocyanins have been isolated from the flowers of Ipomoea congesta R. Brown. One has been previously described as an acylated peonidin derivative. Three others are isomers, derived from peonidin-3-(caffeylsophoroside)-5-glucoside. The fifth was characterised as peonidin-3-(p-coumarylcaffeylsophoroside)-5-glucoside and the last as peonidin-3-(coumarylsophoroside)-5-glucoside. It is noteworthy that the anthocyanins found in this species have the same glycosidic pattern, 3-sophoroside-5-glucoside, as those reported for the cyanidin derivatives in Ipomoea cairica flowers. Acylated anthocyanin occurrence in Tubiflorae order is of chemotaxonomical value.     

Leucine aminopeptidase 3 promotes migration and invasion of breast cancer cells through upregulation of fascin and matrix metalloproteinases-2/9 expression

Overexpression of leucine aminopeptidase 3 (LAP3) is involved in proliferation, migration, and invasion of several tumor cells and plays a crucial role in tumor metastasis. However, the related mechanism remains unknown. In this study, we used MDA-MB-231 and MCF7 breast cancer cell lines to explore the role of LAP3 in the regulation of cancer cell migration and invasion by employing the natural LAP3 inhibitor bestatin and a lentivirus vector that overexpresses or knocks down LAP3. Bestatin inhibited tumor cell migration and invasion in a dose-dependent manner. Western blot assay showed that bestatin and knockdown of LAP3 upregulated phosphorylation of Hsp27 and downregulated expression of fascin. Phosphorylation of Akt and expression of matrix metalloproteinase-2/9 can also be downregulated. LAP3 overexpression showed the opposite results. Immunohistochemistry analysis was conducted to detect expression levels of LAP3 in breast cancer tissues. High LAP3 expression was correlated with the grade of malignancy. Findings of this study uncovered the molecular mechanism of LAP3 on breast cancer metastasis and indicated that LAP3 may act as a potential antimetastasis therapeutic target.     

Differences in the floral anthocyanin content of red petunias and Petunia exserta

In order to resolve a conflict between previous papers regarding the floral anthocyanins of red flowers of Petunia exserta, a naturally occurring species, the HPLC profile of this species was compared with that of commercial red garden petunias. Both HPLC profiles extremely superficially resemble each other in terms of relative amounts and retention times of the major anthocyanins. However, co-elution on HPLC of the mixed sample resulted in clear separation of the components. Three major anthocyanins in red petunias were determined to be cyanidin 3-sophoroside, cyanidin 3-glucoside and peonidin 3-glucoside, which exhibited similar behaviors on HPLC to delphinidin 3-glucoside. delphinidin-3-rutinoside and petunidin 3-rutinoside, respectively, the major floral anthocyanins of P. exserta.     

Phase change modifies anthocyanin synthesis in Acer palmatum Thunb. (Japanese maple) cultivars

The potential markers of juvenility (cyanidin 3-glucoside and cyanidin 3-rutinoside) in autumn leaves of seven Acer palmatum Thunb. cultivars were investigated. Three shoot positions were marked on each cultivar—crown shoot, middle shoot, and basal shoot—and the anthocyanins were analyzed using HPLC-MS. The results showed great differences in cyanidin 3-glucoside and cyanidin 3-rutinoside concentrations among seven cultivars; moreover, significant differences in cyanidin 3-glucoside content levels were also observed among three shoot positions regardless of the cultivar analyzed. The concentration decreased basipetally and reached levels up to 52 times higher in leaves obtained from crown shoots in comparison to basal shoot leaves. Therefore, the content level of cyanidin 3-glucoside can be defined as a quantitative marker of positional effect in all the Acer palmatum Thunb. cultivars analyzed. The content level of cyanidin 3-rutinoside did not express the same positional dependence.     

Isolation and structural determination of 13 flavonoid glycosides in Hibiscus esculentus (okra)

Eleven flavonol glycosides and two anthocyanins, only one of which was previously identified, were isolated from the flower petals of okra, Hibiscus esculentus L. On the basis of chromatographic, spectral, and degradative evidence, the following structural assignments were made: quercetin 4′-glucoside, quercetin 7-glucoside, quercetin 5-glucoside, quercetin 3-diglucoside, quercetin 4′-diglucoside, quercetin 3-triglucoside, quercetin 5-rhamnoglucoside, gossypetin 8-glucoside, gossypetin 8-rhamnoglucoside, gossypetin 3-glucosido-8-rhamnoglucoside, cyanidin 4′-glucoside, and cyanidin 3-glucosido-4′ glucoside. Some evidence was obtained of a pentahy-droxy, monomethoxy-flavone glycoside. The total flavonoid content in the red portion of the petal was 0.48% of fresh weight; that in the white portion was 2.51%. The two anthocyanins comprised 28.5% of the flavonoid content of the red flower but only a trace of the content of the white.