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1.
Curr Issues Mol Biol ; 46(2): 1621-1634, 2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38392223

ABSTRACT

Docetaxel (DTX), a semi-synthetic analogue of paclitaxel (taxol), is known to exert potent anticancer activity in various cancer cells by suppressing normal microtubule dynamics. In this study, we examined how the anticancer effect of DTX is regulated by polyphenols extracted from Korean Artemisia annua L. (pKAL) in DU145 prostate cancer cells (mutant p53) and HCT116 colorectal cancer cells (wild-type p53). Here, we show that the anticancer effect of DTX was enhanced more significantly by pKAL in HCT116 cells than in DU145 cells via phase-contrast microscopy, CCK-8 assay, Western blot, and flow cytometric analysis of annexin V/propidium iodide-stained cells. Notably, mutant p53 was slightly downregulated by single treatment of pKAL or DTX in DU145 cells, whereas wild-type p53 was significantly upregulated by pKAL or DTX in HCT116 cells. Moreover, the enhanced anticancer effect of DTX by pKAL in HCT116 cells was significantly associated with the suppression of DTX-induced p53 upregulation, increase of DTX-induced phospho-p38, and decrease of DTX-regulated cyclin A, cyclin B1, AKT, caspase-8, PARP1, GM130, NF-κB p65, and LDHA, leading to the increased apoptotic cell death and plasma membrane permeability. Our results suggest that pKAL could effectively improve the anticancer effect of DTX-containing chemotherapy used to treat various cancers expressing wild-type p53.

2.
Molecules ; 25(22)2020 Nov 20.
Article in English | MEDLINE | ID: mdl-33233701

ABSTRACT

We previously demonstrated that anthocyanins from the fruits of Vitis coignetiae Pulliat (AIMs) induced the apoptosis of hepatocellular carcinoma cells. However, many researchers argued that the concentrations of AIMs were too high for in vivo experiments. Therefore, we performed in vitro at lower concentrations and in vivo experiments for the anti-cancer effects of AIMs. AIMs inhibited the cell proliferation of Hep3B cells in a dose-dependent manner with a maximum concentration of 100 µg/mL. AIMs also inhibited the invasion and migration at 100 µg/mL concentration with or without the presence of TNF-α. To establish the relevance between the in vitro and in vivo results, we validated their effects in a Xenograft model of Hep3B human hepatocellular carcinoma cells. In the in vivo test, AIMs inhibited the tumorigenicity of Hep3B cells in the xenograft mouse model without showing any clinical signs of toxicity or any changes in the body weight of mice. AIMs inhibited the activation NF-κB and suppressed the NF-κB-regulated proteins, intra-tumoral microvessel density (IMVD) and the Ki67 activity of Hep3B xenograft tumors in athymic nude mice. In conclusion, this study indicates that AIMs have anti-cancer effects (inhibition of proliferation, invasion, and angiogenesis) on human hepatocellular carcinoma xenograft through the inhibition of NF-κB and its target protein.


Subject(s)
Anthocyanins/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , NF-kappa B/metabolism , Plant Extracts/pharmacology , Signal Transduction/drug effects , Vitis/chemistry , Animals , Anthocyanins/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Biomarkers , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Nude , Plant Extracts/chemistry , Xenograft Model Antitumor Assays
3.
Molecules ; 25(16)2020 Aug 09.
Article in English | MEDLINE | ID: mdl-32784919

ABSTRACT

Anthocyanins isolated from Vitis coignetiae Pulliat (Meoru in Korea) (AIMs) have various anti-cancer properties by inhibiting Akt and NF-κB which are involved in drug resistance. Cisplatin (CDDP) is one of the popular anti-cancer agents. Studies reported that MCF-7 human breast cancer cells have high resistance to CDDP compared to other breast cancer cell lines. In this study, we confirmed CDDP resistance of MCF-7 cells and tested whether AIMs can overcome CDDP resistance of MCF-7 cells. Cell viability assay revealed that MCF-7 cells were more resistant to CDDP treatment than MDA-MB-231 breast cancer cells exhibiting aggressive and high cancer stem cell phenotype. AIMs significantly augmented the efficacy of CDDP with synergistic effects on MCF-7 cells. Molecularly, Western blot analysis revealed that CDDP strongly increased Akt and moderately reduced p-NF-κB and p-IκB and that AIMs inhibited CDDP-induced Akt activation, and augmented CDDP-induced reduction of p-NF-κB and p-IκB in MCF-7 cells. In addition, AIMs significantly downregulated an anti-apoptotic protein, XIAP, and augmented PARP-1 cleavage in CDDP-treated MCF-7 cells. Moreover, under TNF-α treatment, AIMs augmented CDDP efficacy with inhibition of NF-κB activation on MCF-7 cells. In conclusion, AIMs enhanced CDDP sensitivity by inhibiting Akt and NF-κB activity of MCF-7 cells that show relative intrinsic CDDP resistance.


Subject(s)
Anthocyanins/pharmacology , Breast Neoplasms/drug therapy , Cisplatin/pharmacology , Drug Resistance, Neoplasm , NF-kappa B/metabolism , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Vitis/chemistry , Antineoplastic Agents/pharmacology , Apoptosis , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Cycle , Cell Movement , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Humans , NF-kappa B/genetics , Proto-Oncogene Proteins c-akt/genetics , Tumor Cells, Cultured
4.
Molecules ; 25(8)2020 Apr 21.
Article in English | MEDLINE | ID: mdl-32326231

ABSTRACT

Artemisia annua L. has been reported to show anti-cancer activities. Here, we determined whether polyphenols extracted from Artemisia annua L. (pKAL) exhibit anti-cancer effects on radio-resistant MDA-MB-231 human breast cancer cells (RT-R-MDA-MB-231 cells), and further explored their molecular mechanisms. Cell viability assay and colony-forming assay revealed that pKAL inhibited cell proliferation on both parental and RT-R-MDA-MB-231 cells in a dose-dependent manner. The anti-proliferative effects of pKAL on RT-R-MDA-MB-231 cells were superior or similar to those on parental ones. Western blot analysis revealed that expressions of cluster of differentiation 44 (CD44) and Oct 3/4, matrix metalloproteinase-9 (MMP-9) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation were significantly increased in RT-R-MDA-MB-231 cells compared to parental ones, suggesting that these proteins could be associated with RT resistance. pKAL inhibited the expression of CD44 and Oct 3/4 (CSC markers), and ß-catenin and MMP-9 as well as STAT-3 phosphorylation of RT-R-MDA-MB-231. Regarding upstream signaling, the JNK or JAK2 inhibitor could inhibit STAT-3 activation in RT-R-MDA-MB-231 cells, but not augmented pKAL-induced anti-cancer effects. These findings suggest that c-Jun N-terminal kinase (JNK) or Janus kinase 2 (JAK2)/STAT3 signaling are not closely related to the anti-cancer effects of pKAL. In conclusion, this study suggests that pKAL exhibit anti-cancer effects on RT-R-MDA-MB-231 cells by suppressing CD44 and Oct 3/4, ß-catenin and MMP-9, which appeared to be linked to RT resistance of RT-R-MDA-MB-231 cells.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Artemisia annua/chemistry , Matrix Metalloproteinase 9/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Plant Extracts/pharmacology , Polyphenols/pharmacology , beta Catenin/metabolism , Antineoplastic Agents, Phytogenic/chemistry , Biomarkers , Biomarkers, Tumor , Breast Neoplasms , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Gene Expression , Humans , Immunophenotyping , Janus Kinase 2/metabolism , Plant Extracts/chemistry , Polyphenols/chemistry , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects
5.
Phytother Res ; 33(5): 1384-1393, 2019 May.
Article in English | MEDLINE | ID: mdl-30887612

ABSTRACT

Evidence suggests that auranofin (AF) exhibits anticancer activity by inhibiting thioredoxin reductase (TrxR). Here, in this study, we have investigated the synergistic effects of AF and morin and their mechanism for the anticancer effects focusing on apoptosis in Hep3B human hepatocellular carcinoma cells. We assessed the anticancer activities by annexin V/PI double staining, caspase, and TrxR activity assay. Morin enhances the inhibitory effects on TrxR activity of AF as well as reducing cell viability. Annexin V/PI double staining revealed that morin/AF cotreatment induced apoptotic cell death. Morin enhances AF-induced mitochondrial membrane potential (ΔΨm) loss and cytochrome c release. Further, morin/AF cotreatment upregulated death receptor DR4/DR5, modulated Bcl-2 family members (upregulation of Bax and downregulation of Bcl-2), and activated caspase-3, -8, and -9. Morin also enhances AF-induced reactive oxygen species (ROS) generation. The anticancer effects results from caspase-dependent apoptosis, which was triggered via extrinsic pathway by upregulating TRAIL receptors (DR4/DR5) and enhanced via intrinsic pathway by modulating Bcl-2 and inhibitor of apoptosis protein family members. These are related to ROS generation. In conclusion, this study provides evidence that morin can enhance the anticancer activity of AF in Hep3B human hepatocellular carcinoma cells, indicating that its combination could be an alternative treatment strategy for the hepatocellular carcinoma.


Subject(s)
Auranofin/pharmacology , Carcinoma, Hepatocellular/drug therapy , Flavonoids/pharmacology , Liver Neoplasms/drug therapy , Animals , Apoptosis/drug effects , Carcinoma, Hepatocellular/pathology , Caspases/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cytochromes c/metabolism , Down-Regulation/drug effects , Humans , Inhibitor of Apoptosis Proteins/metabolism , Liver Neoplasms/pathology , Male , Membrane Potential, Mitochondrial/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Signal Transduction/drug effects , Up-Regulation/drug effects
6.
Phytother Res ; 32(3): 504-513, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29193390

ABSTRACT

Decoctions obtained from the dried flowers of Lonicera japonica Thunb. (Indongcho) have been utilized in folk remedies against inflammatory diseases. Recently, many agents that have used for inflammatory diseases are showing anticancer effects. Here, we have isolated polyphenols extracted from lyophilized Lonicera japonica Thunb (PELJ) and investigated the anticancer effects of PELJ on U937 cells. Here, we demonstrated that PELJ induced apoptosis by upregulation of DR4 and Fas, and further it is augmented by suppression of XIAP. In addition, The PELJ-induced apoptosis is at least in part by blocking PI3K/Akt pathway. These findings suggest that PELJ may provide evidence of anticancer activities on U937 cells. Further study for detailed mechanism and the effects on animal models is warranted to determine whether PELJ provide more conclusive evidence that PELJ which may provide a beneficial effect for treating cancer.


Subject(s)
Caspases/metabolism , Leukemia/metabolism , Lonicera/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Death Domain/metabolism , Apoptosis , Humans , U937 Cells
7.
Asian Pac J Cancer Prev ; 18(11): 2919-2923, 2017 11 26.
Article in English | MEDLINE | ID: mdl-29172259

ABSTRACT

Objective: Anthocyanins belong to a class of flavonoids, exhibiting antioxidant and anti-inflammatory actions have been reported to have anti-cancer effects. Here, we investigated whether anthocyanins can inhibit cancer cell proliferation, invasion, and angiogenesis in human lung cancer A549 cells, which are critically involved in cancer metastasis. Methods: We used anthocyanins from fruits of Vitis coignetiae Pulliat (AIMs) which has been used in Korean folk medicine for the treatment of inflammatory diseases and cancers. We have performed cell proliferation assays, cell invasion assay, gelatin zymography, wound healing assay and western blotting to examine whether anthocyanins can inhibit cancer cell proliferation, invasion, and angiogenesis in A549 cells. Result: AIMs did not inhibit cancer cell proliferation on A549 cells. Also, AIMs suppressed cancer migration, and invasion by supressing MMP-2 and MMP-9 expression. The Immuno-blotting results also revealed that AIMs suppressed the proteins involved in cancer proliferation (COX- 2, C-myc, cyclin D1), migration and invasion (MMP-2, MMP-9), anti-apoptosis (XIAP, and c-IAP2), adhesion and angiogenesis (ICAM-1, VEGF). Conclusion: This study demonstrates that the anthocyanins isolated from fruits of Vitis coignetiae Pulliat inhibit cancer proliferation, cancer migration, and invasion that is involve in cancer-metastasis. This study provides evidence that AIMs might have anti-cancer effects on human lung cancer.

8.
PLoS One ; 12(3): e0174591, 2017.
Article in English | MEDLINE | ID: mdl-28355296

ABSTRACT

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 diphosphate­ribose) 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 B­cell lymphoma­2 (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.


Subject(s)
Apoptosis/drug effects , Arsenicals/pharmacology , Autophagy/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Oxides/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Antineoplastic Agents/pharmacology , Arsenic Trioxide , Blotting, Western , CDC2 Protein Kinase , Cell Line, Tumor , Cell Survival/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinases/metabolism , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Time Factors
9.
Phytother Res ; 30(11): 1824-1832, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27534446

ABSTRACT

Decoctions of the dried flowers of Lonicera japonica Thunb. (Indongcho) have been utilized in folk remedies against various inflammatory diseases, and it is reported neuroprotective effects. The cytokines release from microglia is closely linked to various chronic neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. It is still unknown whether the neuroprotective effects are associated with the antiinflammatory effects. Here, we determined whether polyphenols extracted from lyophilized Lonicera japonica Thunb. (PELJ) would inhibit inflammatory cytokines and mediators. We stimulated microglia with lipopolysaccharide (LPS) to produce inflammatory cytokines, and then assessed the effects of PELJ on these cytokines. PELJ significantly inhibited LPS-induced interleukin-1ß and tumor necrosis factor-α expressions and LPS-induced nitric oxide (NO) and prostaglandin E2 expressions by down-regulating inducible enzyme NO synthase and cyclooxygenase-2 at the protein and mRNA levels. All the suppression of these mediators did not cause any significant cytotoxicity. PELJ also inhibited the nuclear translocation of nuclear factor-kappa B and phosphorylated Akt. These findings suggest that PELJ may offer substantial therapeutic potential for treating inflammatory and neurodegenerative diseases by inhibiting pro-inflammatory cytokines through inhibiting phosphoinositol 3-kinase /Akt/nuclear factor-kappa B signaling pathway. Copyright © 2016 John Wiley & Sons, Ltd.


Subject(s)
Anti-Inflammatory Agents/metabolism , Flavonoids/chemistry , Flowers/chemistry , Lonicera/chemistry , Microglia/cytology , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Tumor Necrosis Factor-alpha/metabolism , Anti-Inflammatory Agents/pharmacology , Signal Transduction
10.
Oncol Rep ; 33(6): 2940-6, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25845556

ABSTRACT

Tetraarsenic hexoxide (As4O6) has been used in Korean traditional medicine for the treatment of cancer since the late 1980's, 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.


Subject(s)
Antineoplastic Agents/administration & dosage , Arsenicals/administration & dosage , Colonic Neoplasms/drug therapy , NF-kappa B/biosynthesis , Oxides/administration & dosage , Animals , Apoptosis/drug effects , Arsenic Trioxide , Cell Line, Tumor , Cell Proliferation/drug effects , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , I-kappa B Kinase/biosynthesis , Mice , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , Phosphorylation , Tumor Necrosis Factor-alpha/biosynthesis
11.
Asian Pac J Cancer Prev ; 16(2): 465-9, 2015.
Article in English | MEDLINE | ID: mdl-25684472

ABSTRACT

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.


Subject(s)
Apoptosis/drug effects , Caspases/metabolism , Crassulaceae/chemistry , Flavonoids/pharmacology , Leukemia/drug therapy , Leukemia/pathology , Plant Extracts/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Blotting, Western , Cell Proliferation/drug effects , Flow Cytometry , Humans , Leukemia/metabolism , Membrane Potential, Mitochondrial/drug effects , Tumor Cells, Cultured
12.
Int J Oncol ; 45(4): 1629-37, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24993541

ABSTRACT

Morin, a flavonoid found in figs and other Moraceae, displays a variety of biological actions, such as anti-oxidant, anti-inflammatory and anti-carcinogenic. However, the anticancer effects of morin and in particular its anti-metastatic effects are not well known. Therefore, in the present study, we investigated the anticancer effects of morin on highly metastatic human breast cancer cells. Our results showed that morin significantly inhibited the colony forming ability of highly metastatic MDA-MB­231 breast cancer cells from low doses (50 µM) without cytotoxicity. In addition, morin changed MDA-MB­231 cell morphology from mesenchymal shape to epithelial shape and inhibited the invasion of MDA-MB­231 cells in a dose-dependent manner. Morin decreased matrix metalloproteinase-9 (MMP-9) secretion and expression of the mesenchymal marker N-cadherin of MDA-MB­231 cells, suggesting that morin might suppress the EMT process. Furthermore, morin significantly decreased the phosphorylation of Akt, and inhibition of the Akt pathway significantly reduced MDA-MB­231 invasion. In an in vivo xenograft mouse model, morin suppressed MDA-MB­231 cancer cell progression. Taken together, our findings suggest that morin exhibits an inhibitory effect on the cancer progression and EMT process of highly metastatic breast cancer cells at least in part through inhibiting Akt activation. This study provides evidence that morin may have anticancer effects against metastatic breast cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Flavonoids/pharmacology , MAP Kinase Signaling System/drug effects , Moraceae/chemistry , Plant Extracts/pharmacology , Animals , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Nude , Neoplasm Invasiveness , Neoplasm Metastasis , Xenograft Model Antitumor Assays
13.
Oncol Rep ; 31(5): 2305-11, 2014 May.
Article in English | MEDLINE | ID: mdl-24627159

ABSTRACT

Arsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980s. Evidence suggests that the anticancer effects of As4O6 are different from those of As2O3. Tumor necrosis factor-α (TNF-α) is generally increased in advanced cancer and is closely related to cancer progression, although it has cancer-killing effects. The reason is that TNF-α activates nuclear factor-κB (NF-κB) that is involved in cell proliferation, invasion, drug resistance and metastasis. In the present study, we investigated the effects of As4O6 on NF-κB activity, NF-κB-mediated cellular responses, and NF-κB-regulated gene expressions involved in metastasis at the concentrations of As4O6 where no cytotoxicity was observed. As4O6 suppressed NF-κB activation in both TNF-α-treated and control cells, and also suppressed IκB phosphorylation in a time-dependent manner, suggesting the suppression of NF-κB results, in part, from the inhibition of IκB degradation. We also confirmed the anti-NF-κB activity of As4O6 with synergism with TNF-α by augmenting caspase-8 activation. As4O6 also suppressed NF-κB activation induced by TNF-α, and some of the downstream NF-κB-regulated proteins involved in cancer proliferation, anti-apoptosis and metastasis. In conclusion, the present study demonstrated that As4O6 has anticancer properties by inhibiting NF-κB activation and NF-κB-regulated proteins at least in part through the inhibition of IκB phosphorylation, especially in the conditions of advanced cancer where TNF-α is highly secreted.


Subject(s)
Arsenicals/pharmacology , Breast Neoplasms/drug therapy , Oxides/pharmacology , Transcription Factor RelA/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Apoptosis/drug effects , Arsenic/pharmacology , Caspase 8/biosynthesis , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm , Enzyme Activation/drug effects , Female , Gene Expression Regulation, Neoplastic , Humans , I-kappa B Kinase/metabolism , MCF-7 Cells , Neoplasm Invasiveness , Neoplasm Metastasis , Phosphorylation/drug effects
14.
Oncol Rep ; 30(5): 2336-42, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24002113

ABSTRACT

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.


Subject(s)
Endothelial Cells/drug effects , Flavonoids/administration & dosage , Neoplasm Invasiveness , Plant Extracts/administration & dosage , Vascular Cell Adhesion Molecule-1/metabolism , Breast Neoplasms , Cell Adhesion/drug effects , Cell Line, Tumor , Citrus/chemistry , Female , Flavonoids/chemistry , Gene Expression Regulation, Neoplastic/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Intercellular Adhesion Molecule-1/metabolism , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/pathology , Plant Extracts/chemistry
15.
Food Chem Toxicol ; 62: 382-9, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24021570

ABSTRACT

Allium cepa Linn is commonly used as supplementary folk remedy for cancer therapy. Evidence suggests that Allium extracts have anti-cancer properties. However, the mechanisms of the anti-cancer activity of A. cepa Linn are not fully elucidated in human cancer cells. In this study, we investigated anti-cancer effects of polyphenols extracted from lyophilized A. cepa Linn (PEAL) in human leukemia cells and their mechanisms. PEAL inhibited cancer cell growth by inducing caspase-dependent apoptosis. The apoptosis was suppressed by caspase 8 and 9 inhibitors. PEAL also up-regulated TNF-related apoptosis-inducing ligand (TRAIL) receptor DR5 and down-regulated survivin and cellular inhibitor of apoptosis 1 (cIAP-1). We confirmed these findings in other leukemic cells (THP-1, K562 cells). In addition, PEAL suppressed Akt activity and the PEAL-induced apoptosis was significantly attenuated in Akt-overexpressing U937 cells. In conclusion, our data suggested that PEAL induced caspase-dependent apoptosis in several human leukemic cells including U937 cells. The apoptosis was triggered through extrinsic pathway by up-regulating DR5 modulating as well as through intrinsic pathway by modulating IAP family members. In addition, 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 leukemia.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Inhibitor of Apoptosis Proteins/metabolism , Onions/chemistry , Phosphoinositide-3 Kinase Inhibitors , Polyphenols/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Ubiquitin-Protein Ligases/metabolism , Caspases/metabolism , Cell Line, Tumor , Humans , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , K562 Cells/drug effects , Leukemia/drug therapy , Leukemia/metabolism , Leukemia/pathology , Phosphatidylinositol 3-Kinases/metabolism , Polyphenols/isolation & purification , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Signal Transduction/drug effects , Ubiquitin-Protein Ligases/antagonists & inhibitors
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