Jeong Won Yun

Characterization of a profile of the anthocyanins isolated from Vitis coignetiae Pulliat and their anti-invasive activity on HT-29 human colon cancer cells.

We isolated anthocyanins from fruits of Vitis coignetiae Pulliat, characterized the anthocyanin profile, and investigated the anti-invasive effects of the anthocyanins on human colon cancer cells. The anthocyanins inhibited cell invasion in a dose-dependent manner, as measured by Matrigel invasion assays, by suppression of matrix metalloproteinase (MMP)-2 and MMP-9 expression. The anti-invasive activity of the anthocyanins was associated with modulation of constitutive nuclear factor kappaB (NF-kappaB) activation. The activation of NF-kappaB triggered by tumor necrosis factor-alpha was also inhibited by the anthocyanins through suppression IkappaBalpha phosphorylation. AIMs inhibited the expression of NF-kappaB-regulated proteins. In conclusion, this study suggested that the anthocyanins isolated from fruits of V. coignetiae Pulliat should have anti-invasive activities on human colon cancer cells and the activities should be related to the inhibition of NF-kappaB-regulated proteins such as MMP-2 and MMP-9 expression through the inhibition of NF-kappaB activation.

Anti-invasive activity of anthocyanins isolated from Vitis coignetiae in human hepatocarcinoma cells.

We investigated anti-invasive effects of the anthocyanins from fruits of Vitis coignetiae Pulliat (known as meoru in Korea) on human hepatoma Hep3B cells. The anthocyanins inhibited cell invasion in a dose-dependent manner as measured by Matrigel (BD Biosciences, San Jose, CA, USA) invasion assays. They also inhibited expression of matrix metalloproteinase (MMP)-2 and MMP-9 and activation of nuclear factor kappaB (NF-kappaB) stimulated by tumor necrosis factor alpha. Taken together, the results of this study indicate that the anthocyanins isolated from fruits of V. coignetiae Pulliat have anti-invasive effects on human hepatoma Hep3B cells and inhibit MMP-2 and MMP-9 gene expression at least in part through the inhibition of NF-kappaB activation.

Flavonoids from Citrus unshiu Marc. inhibit cancer cell adhesion to endothelial cells by selective inhibition of VCAM-1

Citrus fruits have been used as edible fruit and a component of traditional medicine for various diseases including cancer since ancient times. Herein, we investigated the anticancer activity of flavonoids of Citrus unshiu Marc. (FCM) focusing on anti-metastatic effects. We prepared FCM and performed experiments using MDA-MB-231 human breast cancer cells. FCM inhibited TNF-induced cancer cell adhesion to human umbilical vein endothelial cells (HUVECs) without showing any toxicity. FCM inhibited the expression of VCAM-1, but not of ICAM-1, on MDA-MB-231 cells as well as HUVECs. FCM inhibited protein kinase C (PKC) phosphorylation, but not Akt phosphorylation. FCM also inhibited cancer cell invasion in a dose-dependent manner, but not MMP-9 expression. In conclusion, this study suggested that FCM inhibits TNF-induced cancer cell adhesion to HUVECs by inhibiting VCAM-1 through inhibition of PKC, providing evidence that FCM have anti-metastatic activity by inhibiting adhesion molecules and invasion on human breast cancer cells.

The inhibitory effect of anthocyanins on Akt on invasion and epithelial-mesenchymal transition is not associated with the anti-EGFR effect of the anthocyanins

Evidence suggests that anthocyanins inhibit EGFR and Akt activity. However, it is still unknown whether the inhibitory effect of anthocyanins on Akt is associated with the anti-EGFR effect. The effect of anthocyanins on epithelial-mesenchymal transition (EMT) has not been extensively studied. Therefore, we investigated the effects of anthocyanins from fruits of Vitis coignetiae Pulliat (AIMs) on EGF-induced EMT and the underlying molecular mechanisms. AIMs suppressed the invasion of A549 cells in a dose-dependent manner. AIMs inhibited the phosphorylation of Akt and EGFR, but the inhibitory effect on Akt was not derived from EGFR. EGF re-induced Akt phosphorylation at Thr308 in the AIM-treated cells, but not Akt phosphorylation at Ser473. AIMs also inhibited EMT of cancer cells. AIMs inhibited glycogen synthase kinase-3β phosphorylation and β-catenin expression that are invovled in EMT. We confirmed these findings with transforming growth factor (TGF)-β. In conclusion, these data suggest that the inhibitory effect of AIMs on Akt activity is independent of EGFR, and that AIMs suppressed invasion and migration at least in part by suppressing EMT by inhibiting Akt activity as well as EGFR. This study provides evidence that AIMs may have anticancer effects on human cancer cells.

Tetraarsenic Hexoxide Induces Beclin-1-Induced Autophagic Cell Death as well as Caspase-Dependent Apoptosis in U937 Human Leukemic Cells

Tetraarsenic hexaoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980s, and arsenic trioxide (As2O3) is currently used as a chemotherapeutic agent. However, evidence suggests that As4O6-induced cell death pathway was different from that of As2O3. Besides, the anticancer effects and mechanisms of As4O6 are not fully understood. Therefore, we investigated the anticancer activities of As4O6 on apoptosis and autophagy in U937 human leukemic cells. The growth of U937 cells was inhibited by As4O6 treatment in a dose- and a time-dependent manner, and IC50 for As4O6 was less than 2 μM. As4O6 induced caspase-dependent apoptosis and Beclin-1-induced autophagy, both of which were significantly attenuated by Bcl-2 augmentation and N-acetylcysteine (NAC) treatment. This study suggests that As4O6 should induce Beclin-1-induced autophagic cell death as well as caspase-dependent apoptosis and that it might be a promising agent for the treatment of leukemia.

Polyphenols Isolated from Allium cepa L. Induces Apoptosis by Induction of p53 and Suppression of Bcl-2 through Inhibiting PI3K/Akt Signaling Pathway in AGS Human Cancer Cells.

Background: The extract of Allium cepa Linn is commonly used as adjuvant food for cancer therapy. We assumed that it includes a potential source of anti-cancer properties. Methods: We investigated anti-cancer effects of polyphenols extracted from lyophilized A. cepa Linn (PEAL) in AGS human cancer cells. Results: PEAL inhibited cell growth in a dose-dependent manner. It was related to caspase-dependent apoptosis. We confirmed this finding with annexin V staining. PEAL up-regulated p53 expression, and subsequent Bax induction, down regulated Bcl-2 protein, anti-apoptotic protein. In addition, PEAL suppressed Akt activity and PEAL-induced apoptosis were significantly accentuated with Akt inhibitor (LY294002). Conclusions: Our data suggested that PEAL induce caspase-dependent apoptosis through mitochondrial pathway by up-regulating p53 protein, and subsequent Bax protein as well as by modulating Bcl-2 protein, and that PEAL induces caspase-dependent apoptosis at least in part through the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. This study provides evidence that PEAL might be useful for the treatment of cancer.

Anthocyanins from Vitis coignetiae Pulliat Inhibit Cancer Invasion and Epithelial-Mesenchymal Transition, but These Effects Can Be Attenuated by Tumor Necrosis Factor in Human Uterine Cervical Cancer HeLa Cells

Recently we have demonstrated that anthocyanins from fruits of Vitis coignetiae Pulliat (AIMs) have anticancer effects. Here, we investigate the effects of AIMs on cell proliferation and invasion as well as epithelial-mesenchymal transition (EMT) which have been linked to cancer metastasis in human uterine cervical cancer HeLa cells. AIMs inhibited the invasion of HeLa cells in a dose-dependent manner. AIMs inhibited MMP-9 expression in a dose-dependent manner. AIMs inhibited the motility of HeLa cells in a wound healing test. AIMs still suppressed NF-κB activation induced by TNF. AIMs also inhibited EMT in HeLa cells. AIMs suppressed vimentin, N-cadherin, and β-catenin expression and induced E-cadherin. AIMs also suppressed expression of β-catenin and Snail, which was regulated by GSK-3. These effects of AIMs were also limited in the HeLa cells treated with TNF. In conclusion, this study indicates that AIMs have anticancer effects by suppressing NF-κB-regulated genes and EMT, which relates to suppression of IκBα phosphorylation and GSK-3 activity, respectively. However, the effects of AIMs were attenuated in the TNF-high condition.

Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells

Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.

Flavonoids from Orostachys japonicus A. Berger induces caspase-dependent apoptosis at least partly through activation of p38 MAPK pathway in U937 human leukemic cells.

BACKGROUND Orostachys japonicus A. Berger (A. Berger) is commonly used as a folk remedy for cancer therapy. However, the mechanisms of its anti-cancer activity are poorly investigated in human cancer cells. In this study, we investigated whether flavonoids extracted from Orostachys japonicus A. Berger (FEOJ) might have anticancer effects in human leukemia cells, focusing on cell death mechanisms. MATERIALS AND METHODS U937 human leukemic cancer cells were used. RESULTS FEOJ induced apoptosis in a dose-dependent manner in human U937 cancer cells. Flow cytometry revealed significant accumulation of cells with sub-G1 DNA content at the concentrations of 200 μg/mL and 400 μg/mL. FEOJ-induced apoptosis was caspase-dependent through loss of mitochondrial membrane potential (MMP, ΔΨm) in human U937 cancer cells, which might be associated with suppression of Bcl-2 and XIAP proteins. FEOJ induced the p38 MAPK signaling pathway, playing at least in part an important role in FEOJ-induced apoptosis. CONCLUSIONS This study suggested that FEOJ may induce caspase-dependent apoptosis in human leukemic cells by regulating MMP (ΔΨm) through suppressing Bcl-2 and X-IAP. In addition, the results indicated that upstream p38 MAPK signaling regulates the apoptotic effect of FEOJ. This study provides evidence that FEOJ might have anti-cancer potential for human leukemic cells.

Tetraarsenic hexoxide demonstrates anticancer activity at least in part through suppression of NF-κB activity in SW620 human colon cancer cells

Tetraarsenic hexoxide (As4O6) has been used in Korean traditional medicine for the treatment of cancer since the late 1980s, and arsenic trioxide (As2O3) is currently used as a chemotherapeutic agent. Previous studies suggest that the As4O6-induced cell death pathway is different from that of As2O3 and its mechanism of anticancer activity remains unclear. Nuclear factor (NF)-κB is a well-known transcription factor involved in cell proliferation, invasion and metastasis. Hence, in the present study, we investigated the effects of As4O6 on NF-κB activity and NF-κB-regulated gene expression in vitro and in vivo. The cytotoxicity assay revealed that As4O6 inhibited the growth of SW620 cells in a dose-dependent manner, and the half maximal inhibitory concentration (IC50) was ~1 µM after a 48 h treatment. As4O6 suppressed NF-κB activation and suppressed inhibitory κBα (IκBα) phosphorylation stimulated by tumor necrosis factor (TNF). As4O6 also suppressed downstream NF-κB-regulated proteins involved in cancer anti-apoptosis, proliferation, invasion and metastasis. In addition, As4O6 marginally suppressed tumor growth and the anti-NF-κB activity was confirmed using an in vivo xenograft mouse model in which animals were injected with SW620 cells. The present study provides evidence that As4O6 has anticancer properties through suppression of NF-κB activity and NF-κB-mediated cellular responses.