Osthole suppresses hepatocyte growth factor (HGF)-induced epithelial-mesenchymal transition via repression of the c-Met/Akt/mTOR pathway in human breast cancer cells

Substantial activation of the HGF/c-Met signaling pathway is involved in the progression of several types of cancers and associated with increased tumor invasion and metastatic potential. Underlying HGF-induced tumorigenesis, epithelial to mesenchymal transition (EMT) shows a positive correlation with progression in patients. We previously determined that osthole is a potent fatty acid synthase (FASN) inhibitor. FASN is implicated in cancer progression and may regulate lipid raft function. We therefore examined whether osthole could block HGF-induced tumorigenesis by disrupting lipid rafts. Here, we found that osthole could abrogate HGF-induced cell scattering, migration, and invasion in MCF-7 breast cancer cells. Osthole also effectively inhibited the HGF-induced decrease of E-cadherin and increase of vimentin via down-regulation of phosphorylated Akt and mTOR. Interestingly, osthole blocked HGF-induced c-Met phosphorylation and repressed the expression of total c-Met protein in MCF-7 cells. In addition, C75, a pharmacological inhibitor of FASN, repressed the expression of total c-Met protein in MCF-7 cells. Consistent with a role for FASN, loss of c-Met in cells treated with osthole was prevented by the exogenous addition of palmitate. Briefly, our result suggests a connection between FASN activity and c-Met protein expression and that osthole is a potential compound for breast cancer therapy by targeting the major pathway of HGF/c-Met-induced EMT.     

Goniothalamin inhibits growth of human lung cancer cells through DNA damage, apoptosis, and reduced migration ability

We evaluated the possible anticancer performance of a natural compound, goniothalamin (GTN), against human lung cancer using as a non-small cell lung cancer (NSCLC) cell line, H1299, as the model system. Cellular proliferation was significantly inhibited by GTN. Using an improved alkaline comet-nuclear extract (comet-NE) assay, GTN was found to induce a significant increase in the tail DNA. Wound healing and zymography assays showed that GTN attenuated cell migration and caused a reduction in the activity level of two major migration-associated matrix metalloproteinases, MMP-2 and MMP-9. It can be concluded that the DNA-damaging effect of GTN against lung cancer cells leads to growth inhibition as well as a depression in migration ability. Therefore, GTN has potential as a chemotherapeutic agent against lung cancer.     

Diosgenin suppresses hepatocyte growth factor (HGF)-induced epithelial-mesenchymal transition by down-regulation of Mdm2 and vimentin

Substantial activation of the hepatocyte growth factor (HGF)/c-Met pathway leads to cancer cell scattering and invasion and has been observed in several types of cancers, including prostate and colorectal cancers. The phosphorylation cascade downstream of HGF, particularly PI3K/Akt signaling, regulates epithelial-to-mesenchymal transition (EMT). How this signaling governs EMT and whether specific kinases respond to particular EMT effectors remain unclear. This study found specific increases in Mdm2 and vimentin rather than the coregulation of an array of EMT marker proteins in response to HGF-induced EMT in DU145 prostate cancer cells. Importantly, it was further found that diosgenin abrogated HGF-induced DU145 cell scattering and invasion. Moreover, diosgenin effectively inhibited the HGF-induced increases in Mdm2 and vimentin by down-regulating phosphorylated Akt and mTOR. In summary, the results suggest that diosgenin may be a potential compound for use in prostate cancer therapy to target the major HGF-induced EMT pathway.     

Growth inhibition of prostate cancer cells by epigallocatechin gallate in the presence of Cu2+

Green tea is an effective chemopreventive agent to human prostate cancer adenoma (PCA). Epigallocatechin gallate (EGCG) inhibited the growth of PCA cells and induced apoptosis. Cu(2+) is a trace element necessary to our health. Many studies proved that bioactivity of EGCG is altered in the presence of Cu(2+). We investigated the effects of EGCG on PCA cells in the presence of Cu(2+). Also, we explored potential mechanisms via measurement of the relative chemiluminescence of growth medium for PCA cells. Chemiluminscence can be an indication of free radicals. Our test results showed that the addition of EGCG and Cu(2+) to the growth medium decreased the relative viability of androgen-sensitive and androgen-insensitive human prostate cancer cells. However, the effects of EGCG on PCA cells depended on (1) the relative concentrations of added EGCG and Cu(2+) and (2) their order of addition. Our results indicated that few free radicals may be generated in vitro. If so, free radicals generated intracellularly may be a major factor behind apoptosis and growth inhibition observed in the PCA cells. Thus, EGCG might exert its effects intracellularly.     

Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model

A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene could prevent the growth and progression of colorectal tumor in a mouse xenograft model. Bioluminescence imaging, histopathological, immunofluorescence (IFC), and immunohistochemical (IHC) staining results indicated that lycopene could effectively suppress the growth and progression of colon cancer in tumor-bearing mice. The results demonstrated that lycopene significantly suppressed the nuclear expression of PCNA and β-catenin proteins in tumor tissues. Consumption of lycopene could also augment the E-cadherin adherent molecule and nuclear levels of cell cycle inhibitor p21(CIP1/WAF1) protein. The chemopreventive effects of lycopene were associated with suppression of COX-2, PGE(2), and phosphorylated ERK1/2 proteins. Furthermore, the inhibitory effects of lycopene were inversely correlated with the plasma levels of matrix metalloproteinase 9 (MMP-9) in tumor-bearing mice. These results suggested that lycopene could act as a chemopreventive agent against the growth and progression of colorectal cancer in a mouse xenograft model.     

Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumor invasion, and metastasis

Caffeic acid phenethyl ester (CAPE) derived from honeybee propolis has been used as a folk medicine and has several proven biological activities. The present study investigated the effect of CAPE on angiogenesis, tumor invasion, and metastasis. A cytotoxicity assay of CAPE in CT26 colon adenocarcinoma cells showed a dose-dependent decrease in cell viability but no significant influence on the growth of human umbilical vein epithelial cells (HUVEC). A low concentration of CAPE (1.5 microg/mL) inhibited 52.7% of capillary-like tube formation in HUVEC culture on Matrigel. CAPE (6 microg/mL)-treated CT26 cells showed not only inhibited cell invasion by 47.8% but also decreased expression of matrix metalloproteinase (MMP)-2 and -9. Vascular endothelial growth factor (VEGF) production from CT26 cells was also inhibited by treatment with CAPE (6 microg/mL). Intraperitoneal injection of CAPE (10 mg/kg/day) in BALB/c mice reduced the pulmonary metastatic capacity of CT26 cells accompanied with a decreased plasma VEGF level. CAPE treatment also prolonged the survival of mice implanted with CT26 cells. These results indicate that CAPE has potential as an antimetastatic agent.     

Metabolic fate of (-)-[4-(3)H]epigallocatechin gallate in rats after oral administration

After oral administration of [4-(3)H]EGCg to rats, the radioactivity in blood, major tissues, urine, and feces was measured over time. The radioactivity in blood and most tissues remained low for 4 h postdose, began to increase after 8 h, peaked at 24 h, and then decreased. Major urinary excretion of radioactivity occurred in the 8-24 h period, and the cumulative radioactivity excreted by 72 h was 32.1% of the dose. The radioactivity in the feces was 35.2% of the dose within 72 h postdose. In the case of rats pretreated with antibiotics (antibiotic-pretreated rats), the radioactivity levels of the blood and urine were definitely lower than those in rats not pretreated with antibiotics (normal rats). The radioactivity recovered in the antibiotic-pretreated rat urine was estimated to be only (1)/(100) of that in the normal rat urine. These results clearly demonstrated that the radioactivity detected in the blood and urine of normal rats mostly originated from degradation products of EGCg produced by intestinal bacteria. Furthermore, a main metabolite in the normal rats was purified and identified as 5-(5'-hydroxyphenyl)-gamma-valerolactone 3'-O-beta-glucuronide (M-2). In feces of the normal rats, EGC (40.8% of the fecal radioactivity) and 5-(3',5'-dihydroxyphenyl)-gamma-valerolactone (M-1, 16.8%) were detected. These results suggested that M-1 was absorbed in the body after degradation of EGCg by intestinal bacteria, yielding M-1 with EGC as an intermediate. Furthermore, M-2 was thought to be formed from M-1 in the intestinal mucosa and/or liver, then to enter the systemic circulation, and finally to be excreted in the urine. Taking into account all of the above findings, a possible metabolic route of EGCg orally administered to rats is proposed.     

Inhibition of xanthine oxidase and suppression of intracellular reactive oxygen species in HL-60 cells by theaflavin-3,3'-digallate, (-)-epigallocatechin-3-gallate, and propyl gallate

The inhibitory effects of five tea polyphenols, namely theaflavin (TF1), theaflavin-3-gallate (TF2), theaflavin-3,3'-digallate (TF3), (-)-epigallocatechin-3-gallate (EGCG), and gallic acid, and propyl gallate (PG) on xanthine oxidase (XO) were investigated. These six antioxidant compounds reduce oxidative stress. Theaflavins and EGCG inhibit XO to produce uric acid and also act as scanvengers of superoxide. TF3 acts as a competitive inhibitor and is the most potent inhibitor of XO among these compounds. Tea polyphenols and PG all have potent inhibitory effects (>50%) on PMA-stimulated superoxide production at 20 approximately 50 microM in HL-60 cells. Gallic acid (GA) showed no inhibition under the same conditions. At 10 microM, only EGCG, TF3, and PG showed significant inhibition with potency of PG > EGCG > TF3. The superoxide scavenging abilities of these six compunds are as follows: EGCG > TF2 > TF1 > GA > TF3 > PG. PG was the most potent inhibitor of PMA-stimulated H(2)O(2) production in HL-60 cells. The order of H(2)O(2) scavenging ability was TF2 > TF3 > TF1 > EGCG > PG > GA. Therefore, the antioxidative activity of tea polyphenols and PG is due not only to their ability to scavenge superoxides but also to their ability to block XO and related oxidative signal transducers.     

Isolation and characterization of a new compound from Prunus mume fruit that inhibits cancer cells

An active compound that inhibits cancer cells was isolated from the fruit of Prunus mume, and its structure and in vitro activities were characterized. The n-hexane fraction obtained from methanol extracts exhibited the strongest inhibitory effect on the growth of cancer cells. From the n-hexane fraction, a new compound named B-1 was purified through preparative thin-layer chromatography, ODS column chromatography, and reverse phase high-performance liquid chromatography and its structure was analyzed by fast atom bombardment mass spectrometry and 1H and 13C NMR. The molecular formula of B-1 was C19H22O6 {2-hydroxy-1-[(7-hydroxy-2-oxo-2H-chromen-6-yl)methyl]-2-methylpropyl-(2Z)-3-methyl-but-e-enoate:prunate}, and the IC50 value was in the range of 39-58 microg/mL in descending order of the cancer cell lines Hep-2, SW-156, HEC-1-B, and SK-OV-3. B-1 exhibited 81-96% inhibition at a concentration level of 100 microg/mL against all cells, based on an 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. However, B-1 showed little effect against normal cells with only 23% or less growth inhibition at 100 microg/mL. Thus, B-1 has a highly specific inhibitory effect against cancer cells but little effect against normal cells. When the cancer cell lines Hep-2 and SK-OV-3 were incubated with B-1 for 72 h, most of the tested cells suffered strong growth inhibition. The compound has the potential to be developed as a nutraceutical.     

苗期与拔节期淹涝抑制夏玉米生长发育、降低产量

为了探明夏玉米对不同淹涝时期与历时的响应规律,采用防雨棚下有底测坑试验在夏玉米的苗期、拔节期、抽雄吐丝期和灌浆期分别设置不同的淹涝天数(2、4、6、8、10d),分析了淹涝时期与历时对夏玉米生长发育及产量性状的影响。研究结果表明,淹涝对夏玉米株高的影响随着淹涝时期的后移而减小,苗期淹涝对株高影响最大,拔节期次之,抽雄吐丝期影响较小,且随着淹涝历时的增加株高呈降低趋势,而灌浆期淹涝对株高无显著性影响。苗期淹涝解除后,因玉米前期的补偿生长能力强,受涝处理的株高与对照(CK)间的差异随生育进程的推进逐渐减少;而拔节期淹涝植株的补偿生长能力较弱,各处理灌浆期的株高与CK间的差异仍较大。不同淹涝处理下叶面积指数(LAI)的变化趋势与株高一致,任一生育期发生淹涝,其LAI随着淹涝历时的增加逐渐降低。与CK相比,苗期、拔节期、抽雄吐丝期和灌浆期淹涝使株高和LAI平均分别降低5.49%～45.26%、2.38%～35.62%、1.60%～8.23%、0.63%～5.15%和17.36%～62.42%、14.81%～46.56%、4.40%～17.34%、1.97%～15.39%。淹涝对夏玉米生长发育进程也具有明显影响,特别是在生长前期,苗期淹涝对玉米生育进程的影响最大,其次为拔节期,抽雄吐丝期影响很小,灌浆期无影响。此外,任一生育阶段发生淹涝,其果穗长、出籽率、穂粒质量、穗粒数、百粒质量和产量均随淹涝历时的增加呈降低趋势;苗期、拔节期、抽雄期和灌浆期淹涝分别减产17.98%～54.97%、9.12%～100%、2.58%～28.63%和5.93%～20.28%,其淹涝历时分别达到2、4、6、4d时就会造成显著减产,减产率分别为17.98%、21.34%、12.99%和13.52%。可见苗期和拔节期是夏玉米淹涝的关键时期,生产上应避免该生育期发生淹涝。该研究可为对夏玉米农田排水方案的合理制定、洪涝灾害损失的评估以及抗灾减灾能力的提高提供参考。     

Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro

Berry fruits are widely consumed in our diet and have attracted much attention due to their potential human health benefits. Berries contain a diverse range of phytochemicals with biological properties such as antioxidant, anticancer, anti-neurodegerative, and anti-inflammatory activities. In the current study, extracts of six popularly consumed berries--blackberry, black raspberry, blueberry, cranberry, red raspberry and strawberry--were evaluated for their phenolic constituents using high performance liquid chromatography with ultraviolet (HPLC-UV) and electrospray ionization mass spectrometry (LC-ESI-MS) detection. The major classes of berry phenolics were anthocyanins, flavonols, flavanols, ellagitannins, gallotannins, proanthocyanidins, and phenolic acids. The berry extracts were evaluated for their ability to inhibit the growth of human oral (KB, CAL-27), breast (MCF-7), colon (HT-29, HCT116), and prostate (LNCaP) tumor cell lines at concentrations ranging from 25 to 200 micro g/mL. With increasing concentration of berry extract, increasing inhibition of cell proliferation in all of the cell lines were observed, with different degrees of potency between cell lines. The berry extracts were also evaluated for their ability to stimulate apoptosis of the COX-2 expressing colon cancer cell line, HT-29. Black raspberry and strawberry extracts showed the most significant pro-apoptotic effects against this cell line. The data provided by the current study and from other laboratories warrants further investigation into the chemopreventive and chemotherapeutic effects of berries using in vivo models.     

Cancer chemopreventive effects of lycopene: suppression of MMP-7 expression and cell invasion in human colon cancer cells

Clinical studies indicate that high blood levels of leptin or matrix metalloproteinase-7 (MMP-7; matrilysin) proteins are associated with tumor progression of human colorectal cancer (CRC). Leptin could play an important role in cell migration and invasion of cancer cells. Our previous study indicated that lycopene could inhibit the proliferation of human colon cancer cells in vitro. However, the inhibitory effects of lycopene on the progression of human colon cancer cells have not been demonstrated yet. In this study, we investigated the inhibitory effects of lycopene on tumor progression including cell invasion and MMP-7 expression in leptin-stimulated human colon cancer cells in vitro. Our results demonstrated that lycopene significantly inhibited leptin-mediated cell invasion and MMP-7 expression in human colon cancer HT-29 cells. Lycopene could augment the expression and stability of E-cadherin proteins. Our results showed that MAPK/ERK and PI3K/Akt signaling pathways played important roles in leptin-mediated MMP-7 expression and cell invasion. Lycopene could effectively inhibit the phosphorylation of Akt, glycogen synthase kinase-3β (GSK-3β) and ERK 1/2 proteins. The molecular mechanisms of lycopene were in part through decreases in nuclear levels of AP-1 and β-catenin proteins. These novel findings suggested that lycopene could act as a chemopreventive agent to suppress MMP-7 expression and leptin-mediated cell invasion in human colon cancer HT-29 cells.     

(-)-Anonaine induces DNA damage and inhibits growth and migration of human lung carcinoma h1299 cells

The anticancer effects of (-)-anonaine were investigated in this current study. (-)-Anonaine at concentration ranges of 50-200 μM exhibited significant inhibition to cell growth and migration activities on human lung cancer H1299 cells at 24 h, albeit cell cycle analyses showed that (-)-anonaine at the above concentration ranges did not cause any significant changes in cell-cycle distributions. Significant nuclear damages of H1299 cells were observed with 10-200 μM (-)-anonaine treatment in a comet assay, whereas higher concentrations (6 and 30 mM) of (-)-anonaine concentrations were required to cause DNA damages in an in vitro plasmid cleavage assay. In summary, our results demonstrated that (-)-anonaine exhibited dose-dependent antiproliferatory, antimigratory, and DNA-damaging effects on H1299 cells. We inferred that (-)-anonaine can cause cell-cycle arrest and DNA damage to hamper the physiological behavior of cancer cells at 72 h, and therefore, it can be useful as one of the potential herbal supplements for chemoprevention of human lung cancer.     

Antitumor activity of capsaicin on human colon cancer cells in vitro and colo 205 tumor xenografts in vivo

Capsaicin was reported to inhibit cancer cell growth. The aim of this study was to evaluate the antitumor potential of capsaicin by studying antitumor activity in vitro as well as in vivo. The in vitro studies are to examine the effects of capsaicin on human colon cancer colo 205 cells after exposure to capsaicin. The results showed that capsaicin induced cytotoxic effects in a time- and dose-dependent manner and increased reactive oxygen species (ROS) and Ca(2+) but decreased the level of mitochondrial membrane potential (ΔΨ(m)) in colo 205 cells. Data from Western blotting analysis indicated that the levels of Fas, cytochrome c, and caspases were increased, leading to cell apoptosis. Capsaicin decreased the levels of anti-apoptotic proteins such as Bcl-2 and increased the levels of pro-apoptotic proteins such as Bax. Capsaicin-induced apoptosis in colo 205 cells was also done through the activations of caspase-8, -9 and -3. In vivo studies in immunodeficient nu/nu mice bearing colo 205 tumor xenografts showed that capsaicin effectively inhibited tumor growth. The potent in vitro and in vivo antitumor activities of capsaicin suggest that capsaicin might be developed for the treatment of human colon cancer.     

Aluminum inhibits growth and stability of cortical microtubules in wheat (Triticum aestivum) roots

Aluminum (Al) occurs abundantly in soil and solubilized aluminum ions in acid soil inhibit plant growth, in particular, root growth. Although several toxic effects of Al on plant growth have been reported, the mechanism of Al toxicity remains to be clarified.     

3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid, an active principle of kimchi, inhibits development of atherosclerosis in rabbits

The effects of 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA) originating from Korean cabbage kimchi were investigated, showing an antioxidant effect on the prevention of atherosclerosis in hypercholesterolemic rabbits. Twenty-one 3-month-old rabbits were fed an atherogenic diet containing 0.5% (w/w) cholesterol and 10% (w/w) coconut oil, whereas another two groups were given an atherogenic diet with intravenous injection of either HDMPPA or simvastatin (0.33 mg/kg/day) for 4 weeks. HDMPPA inhibited the oxidative modification of low-density lipoprotein (IC 50 = 1.4 microg/mL) and increased 2,2'-diphenyl-1-picrylhydrazyl radical scavenging activity (IC 50 = 0.78 microg/mL) in a dose-dependent manner. In hypercholesterolemic rabbits, the thickness of intima of aorta of the HDMPPA group was significantly reduced (control versus HDMPPA, 42%; simvastatin, 38%) without a plasma cholesterol-lowering effect. Thiobarbituric acid reactive substance formation in the plasma of the HDMPPA group was significantly decreased compared to that of the control group. Furthermore, the generation of vascular reactive oxygen species in HDMPPA group was suppressed as the cyclooxygenase-2 protein level decreased. These findings suggest that HDMPPA prevents the development of aortic atherosclerosis in high-cholesterol-fed rabbits. The antiatherosclerotic effect of HDMPPA may be due to an antioxidative effect at a low dose without cholesterol-lowering effects.     

Germination,growth and starch breakdown in Cl3 Fe pretreated pea and barley seeds

Pea and barley seeds were soaked for 3 hours in Cl₃Fe solutions of 0, 50, 500, 2500 and 5000 ppm of iron. The influence of this pretreatment on germination, seedlings growth and starch breakdown was subsequently determined. These results were related to the capacity of iron accumulation in seeds and it subsequent transport to the seedlings.