Qinglong Guo

China Pharmaceutical University, Nan-ching-hsü, Jiangxi Sheng, China

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Publications (99)306.66 Total impact

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    ABSTRACT: Wogonin, a flavonoid derived from Scutellaria baicalensis Georgi, has been demonstrated to be highly effective in treating hematologic malignancies. In this study, we investigated the anticancer effects of wogonin on K562 cells, K562 imatinib-resistant cells, and primary patient-derived CML cells. Wogonin up-regulated transcription factor GATA-1 and enhanced binding between GATA-1 and FOG-1, thereby increasing expression of erythroid-differentiation genes. Wogonin also up-regulated the expression of p21 and induced cell cycle arrest. Studies employing benzidine staining and analyses of cell surface markers glycophorin A (GPA) and CD71 indicated that wogonin promoted differentiation of K562, imatinib-resistant K562, and primary patient-derived CML cells. Wogonin also enhanced binding between GATA-1 and MEK, resulting in inhibition of the growth of CML cells. Additionally, in vivo studies showed that wogonin decreased the number of CML cells and prolonged survival of NOD/SCID mice injected with K562 and imatinib-resistant K562 cells. These data suggested that wogonin induces cycle arrest and erythroid differentiation in vitro and inhibits proliferation in vivo.
    Oncotarget 08/2014; · 6.64 Impact Factor
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    ABSTRACT: This study was aimed at investigating the reversal effect of oroxylin A, a naturally bioactive monoflavonoid separated and purified from S. baicalensis Georgi, in human chronic myeloid leukemia (CML) and the underlying mechanisms. The results showed that CXCL12 could enhance the resistance of K562 cells to adriamycin (ADM) by increasing the expression of CXCR4, up-regulating the downstream PI3K/Akt pathway, and promoting translocation of NF-κB dimers into nucleus and subsequently decreasing the expression of apoptosis-related proteins in K562 cells. And we found that ADM resistance was partially reversed by CXCR4 siRNA transfection. Moreover, the sensitivity enhancement of oroxylin A was demonstrated by decreasing the expression of CXCR4 at both protein and mRNA levels, via PI3K/Akt/NF-κB pathway and triggering the apoptosis pathway in vitro. In addition, the in vivo study showed that oroxylin A increased apoptosis of leukemic cells with low systemic toxicity, and the mechanism was the same as in vitro study. In conclusion, all these results showed that oroxylin A improved the sensitivity of K562/ADM cells by increasing apoptosis in leukemic cells and decreasing the expression of CXCR4 and PI3K/Akt/NF-κB pathway, and probably served as a most promising agent for CML treatment.
    Biochemical pharmacology. 05/2014;
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    ABSTRACT: In multiple myeloma (MM), the hypoxic environment is an important factor causing tumor angiogenesis which is strongly correlated to disease progression and unfavorable outcome by activating the key transcription factor, hypoxia-inducible factor-1α (HIF-1α). Gambogic acid (GA) is the major active ingredient of gamboge, which has been shown to possess antitumor effect by in vitro and in vivo study. However, the underlying molecular mechanism that whether GA inhibits tumor angiogenesis remains not well understood. In this study, we investigated the effects of GA on expression of HIF-1α, and its downstream target gene vascular endothelial growth factor (VEGF) in human MM U266 cells. We found that hypoxia induced increase in the level of HIF-1α subunit protein and activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target protein of rapamycin (mTOR) pathway. Moreover, the treatment with GA markedly decreased HIF-1α and VEGF expression under hypoxic condition. Mechanistic studies exhibited that GA inhibited the production of HIF-1α by reducing phosphorylation of Akt and mTOR in U266 cells. Furthermore, in vivo study revealed that intravenous injection of GA once every other day for two weeks could suppress tumor volumes by antiangiogenesis activity. Taken together, our results identify GA suppress hypoxia-activated pathways that linked to MM progression, at least partly, by the inhibition of PI3K/Akt/mTOR signaling pathway. Therefore, GA may be a new potent therapeutic agent against human MM cells.This article is protected by copyright. All rights reserved.
    Cancer Science 05/2014; · 3.48 Impact Factor
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    ABSTRACT: Tumor invasion and migration obstructs the treatment and prognosis of cancer. In this research, we investigated the effect of oroxylin A, a natural compound extracted from Scutellaria radix, the root of Scutellaria baicalensis, on inhibition of the invasion and migration of three different tumor cell lines: MCF-7, DU145, and HepG2. The results suggested that oroxylin A could inhibit hypoxia-induced migration and invasion of the three cell lines mentioned above. To study the detailed mechanisms, studies were carried out on MCF-7 cells and it was found that oroxylin A could regulate the expression of related markers in MCF-7 cells including E-cadherin, N-cadherin, and Vimentin. It was also found that oroxylin A inhibited the hypoxia-induced invasion and migration of MCF-7 cells by suppressing the Notch pathway. Oroxylin A inhibited N1ICD translocating to the nucleus and binding to epithelial-mesenchymal transition-related transcription factor Snail, thus suppressing the invasion and migration of MCF-7 cells. Therefore, oroxylin A is expected to be a promising candidate for antimetastasis treatment through suppression of the hypoxia-induced Notch pathway.
    Anti-cancer drugs 03/2014; · 2.23 Impact Factor
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    ABSTRACT: Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been demonstrated possessing anti-metastatic activity in vitro and in vivo. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein negatively regulating matrix metalloproteinases (MMPs), plays an important role in tumor invasion and metastasis. The present study investigates the regulatory effect of GA on RECK expression and the role of RECK in GA-induced anti-invasion in A549 human lung cancer cells. Our results showed that GA dose-dependently inhibited cell invasion and suppressed A549 experimental lung metastasis in vivo, which was attributed to RECK up-regulation at both protein and mRNA levels. With small interference RNA (siRNA) blocking RECK expression, we found inhibition of RECK decreased the GA-induced inhibition of MMP-2/9, which was in consistent with the attenuated anti-invasive effect of GA. Further study indicated that GA effectively suppressed Histone deacetylase (HDAC) 1/specificity protein (Sp) 1 binding and Sp1 phosphorylation associating with Extracellular signal-regulated kinases (ERK) signaling blocking, leading to RECK up-regulation. Taken together, these data demonstrate that RECK contributes to GA's anti-invasive activity and provide new evidence for GA being served as a therapeutic candidate for cancer metastasis. © 2014 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 02/2014; · 4.27 Impact Factor
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    ABSTRACT: Baicalein (5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one), a major flavonoid extracted from the root of Scutellaria baicalensis Georgi (Chinese name: Huangqin), showed potent anti-proliferative activity against a broad panel of human cancer cell lines both in vitro and in vivo. A novel series of baicalein derivatives were synthesized by introducing a group to C6-OH and a nitrogen-containing hydrophilic heterocyclic ring to C7-OH via a length of 3 or 4-carbon chain in this study. The in vitro antiproliferative activities of the 30 derivatives against HepG2, A549, BCG-823 cancer cell lines were evaluated. Among them, 10 compounds exhibit more potent cytotoxicity than baicalein against the three cancer cell lines. The most potent compound 9b possesses highest anti-proliferative potency against HepG2, A549, and BCG-823 with an IC50 value of 2.0μM, 0.8μM and 3.2μM, respectively. Preliminary mechanism studies with compound 9b using Annexin V/PI double-staining assay and DAPI staining assay indicated that 9b inhibits tumor cell proliferation potentially through inducing apoptosis.
    Bioorganic & medicinal chemistry letters 01/2014; · 2.65 Impact Factor
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    ABSTRACT: Cancer cell invasion, one of the crucial events in local growth and metastatic spread of tumors, possess a broad spectrum of mechanisms, especially altered expression of matrix metalloproteinases. LFG-500 is a novel synthesized flavonoid with strong anti-cancer activity, whose exact molecular mechanism remains incompletely understood. This current study was designed to examine the effects of LFG-500 on tumor metastasis using in vitro and in vivo assays. LFG-500 could inhibit adhesion, migration and invasion of MDA-MB-231 human breast carcinoma cells. Meanwhile, it reduced the activities and expression of MMP-2 and MMP-9 via suppressing the transcriptional activation of NF-κB rather than AP-1 or STAT3. Moreover, LFG-500 repressed TNF-α induced cell invasion through inhibiting NF-κB and subsequent MMP-9 activity. Further elucidation of the mechanism revealed that PI3K/AKT but not MAPK signaling pathway was involved in the inhibitory effect of LFG-500 on NF-κB activation. LFG-500 could also suppress lung metastasis of B16F10 murine melanoma cells in vivo. Taken together, these results demonstrated that LFG-500 could block cancer cell invasion via down-regulation of PI3K/AKT/NF-κB signaling pathway, which provides new evidence for the anti-cancer activity of LFG-500.
    PLoS ONE 01/2014; 9(3):e91332. · 3.73 Impact Factor
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    ABSTRACT: Wogonin, a natural monoflavonoid extracted from Scutellariae radix, has been reported for its ability of inhibiting tumor angiogenesis. In this study, we assessed the effect of wogonin on angiogenesis induced by low level of H2O2 (10 μM) in human umbilical vein endothelial cells (HUVECs). Wogonin suppressed H2O2-induced migration and tube formation of HUVECs as well as microvessle sprouting from rat aortic rings in vitro. Meanwhile, wogonin suppressed vessels growth in chicken chorioallantoic membrane (CAM) model in vivo. Mechanistic studies showed that wogonin suppressed H2O2-activated PI3K/Akt pathway and reduced the expression of vascular endothelial growth factor (VEGF) up-regulated by H2O2 in both protein and mRNA levels. In addition, wogonin also inhibited nuclear translocation of NF-κB, and decreased the binding ability of NF-κB with exogenous consensus DNA oligonucleotide. Then we further invesitigated the effect of wogonin on over-activated PI3K/Akt pathway by insulin-like growth factor-1 (IGF-1) and H2O2. We found wogonin suppressed phosphorylation of Akt, up-regulation of VEGF and angiogenesis in vitro which was further induced by IGF-1 and H2O2. Moreover, in NF-κB overexpressed HUVECs, wogonin could also reduce the expression of VEGF and inhibited the migration and tube formation. Taken together, these results suggested that wogonin was potential in inhibiting H2O2-induced angiogenesis in vitro and in vivo via suppressing PI3K/Akt pathway and NF-κB signaling.
    Vascular Pharmacology 01/2014; · 3.21 Impact Factor
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    ABSTRACT: In this study, the anticancer effect of LW-214, a newly synthesized flavonoid, against MCF-7 human breast cancer cells and the underlying mechanisms were investigated. LW-214 triggered the mitochondrial apoptotic pathway by increasing Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (ΔΨm) and caspase-9 activation, degradation of poly (ADP-ribose) polymerase (PARP), cytochrome c (Cyt c) release and apoptosis-inducing factor (AIF) transposition. Further research revealed that both the reactive oxygen species (ROS) generation and the apoptosis signal regulating kinase 1 (ASK1) activation by LW-214 were induced by down-regulating the thioredoxin-1 (Trx-1) expression. The ROS elevation and ASK1 activation induced a sustained phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125, as known as JNK inhibitor, almost reversed LW-214-induced apoptosis in MCF-7 cells. Overexpression of Trx-1 in MCF-7 cells attenuated LW-214-mediated apoptosis as well as the JNK activation and reversed the expression of mitochondrial apoptosis-related protein. Accordingly, the in vivo study showed that LW-214 exhibited a potential antitumor effect in BALB/c species mice inoculated MCF-7 tumor with low systemic toxicity, and the mechanism was the same as in vitro study. Taken together, these findings indicated that LW-214 may down-regulated Trx-1 function, causing intracellular ROS generation and releasing the ASK1, and lead to JNK activation, which consequently induced the mitochondrial apoptosis in vitro and in vivo.
    Biochemical pharmacology 12/2013; · 4.25 Impact Factor
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    ABSTRACT: Wogonin, a flavone from the root of Scutellaria baicalensis Georgi, has shown various biological activities. In our previous study, it was confirmed that wogonin could decrease the expression of hypoxia-inducible factor-1α (HIF-1α) by affecting its stability under hypoxia. However, it is still unknown whether wogonin could influence Wnt/β-catenin pathway under hypoxia. In this study, we found that wogonin disrupted Wnt/β-catenin signaling and reduced the secretion of vascular endothelial growth factor (VEGF, also known as vascular permeability factor, VPF), which increased vascular permeability in certain diseases. It was found that wogonin suppressed HUVECs hyperactivity and actin remodeling induced by hypoxia, inhibited transendothelial cell migration of the human breast carcinoma cell MDA-MB-231 and the extravasated Evans in vivo Miles vascular permeability assay. Wogonin-treated cells showed a decrease in the expression of Wnt protein and its co-receptors, as well as a parallel increase in the expression of Axin and GSK-3β in degradation complex, leading to degradation of β-catenin. In addition, wogonin promoted the binding between Axin and β-catenin, increased ubiquitination of β-catenin and promoted its degradation. Interestingly, wogonin decreased the expression of TCF-1, TCF-3, and LEF-1 and inhibited nuclear accumulation of β-catenin as well as the binding of β-catenin and TCF-1, TCF-3, or LEF-1. All of the above results showed that wogonin could inhibit the expression of VEGF, which is an important factor regulated by β-catenin. Taken together, the results suggested that wogonin was a potent inhibitor of Wnt/β-catenin and influenced vascular permeability, and this might provide new therapeutics in certain diseases. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 10/2013; · 4.27 Impact Factor
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    ABSTRACT: Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1 and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1β and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. 41 derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.
    Journal of Medicinal Chemistry 09/2013; · 5.61 Impact Factor
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    ABSTRACT: Oroxylin A (OA) is a flavonoid derived from a Chinese herb that has previously been reported to inhibit the proliferation of several cancer cell lines. It is found that OA significantly inhibited the growth of myeloid leukemia cell lines and as xenografts in immunodeficient mice and primary blasts from acute myelogenous leukemia (AML) patients. Furthermore, OA-induced cell cycle arrest and differentiation were observed in OA-treated AML cell lines. OA-induced increase of CD11b/CD14 expression was reversed by GW9662, a specific PPARγ inhibitor, or transient transfection with PPARγ siRNA. Docking study showed OA bound to ligand-binding-domain of PPARγ via forming hydrogen bonds with Arg288 and Leu340 sites. Results of FP-based ligand assay verified PPARγ binding activity of OA, and in OA-treated cells, intranuclear accumulation and increased binding activity of PPARγ to PPRE were detected. We also found GW9662 attenuated OA-induced up-regulation of C/EBPβ, an important regulator of leukemic differentiation, and p21 which is a potent inhibitor of CDKs that can inhibit phosphorylation of Rb by cyclin D1-CDK4 complexes. Moreover, our results showed that OA displayed synergistic effects with ATRA and VD3 in part related to reduction of intranuclear phosphorylated RXRα that has been reported to block nuclear receptor/RXRα heterodimer transcriptional activity. This reduction of phosphorylated RXRα was associated with inhibition of the specific upstream MAP kinase ERK1/2. We suggest that OA may provide a novel complement to AML treatment by its dual effects of augmenting PPARγ activity and sensitizing nuclear receptors to specific ligands. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 08/2013; · 6.20 Impact Factor
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    ABSTRACT: Wogonin, a naturally occurring mono-flavonoid, has been reported to have tumor therapeutic potential and good selectivity both in vitro and in vivo. Herein, we investigated the anti-proliferation effects and associated mechanisms of wogonin in human colorectal cancer in vitro. The flow-cytometric analysis showed that wogonin induced a G1 phase cell cycle arrest in HCT116 cells in a concentration- and time-dependent manner. Meanwhile, the cell cycle-related proteins, such as Cyclin A, E, D1, and CDK2, 4 were down-regulated in wogonin-induced G1 cell cycle arrest. Furthermore, we showed that the anti-proliferation and G1 arrest effect of wogonin on HCT116 cells was associated with deregulation of Wnt/β-catenin signaling pathway. Wogonin-treated cells showed decreased intracellular levels of Wnt proteins, and activated degradation complex to phosphorylated and targeted β-catenin for proteasomal degradation. Wogonin inhibited β-catenin-mediated transcription by interfering in the transcriptional activity of TCF/Lef, and repressing the kinase activity of CDK8 which has been considered as an oncogene involving in the development of colorectal cancers. Moreover, CDK8 siRNA-transfected HCT116 cells showed similar results to wogonin treated cells. Thus, our data suggested that wogonin induced anti-proliferation and G1 arrest via Wnt/β-catenin signaling pathway and it can be developed as a therapeutic agent against human colorectal cancer.
    Toxicology 07/2013; · 4.02 Impact Factor
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    ABSTRACT: Malignant gliomas are the most common and most aggressive primary brain tumor, and for which differentiation therapy has emerged as a promising candidate strategy. In this study, we used in vitro and in vivo assays to examine the differentiation effects of wogonin, a major active constituent of Scutellaria baicalensis, on glioma C6 and U251 cells. We found that wogonin can suppress cell proliferationin and induce G0/G1 arrest under a concentration-dependent manner. Wogonin also triggered significant reduction in the G1 cell-cycle regulatory proteins cyclin D1, cyclin-dependent kinase 2 and 4 along with overexpression of cell-cycle inhibitory proteins p27. Immunofluorescence and western blot analysis indicated that wogonin increased the expression of lineage-specific differentiation markers glial fibrillary acidic protein (GFAP). In mechanisms, we verified that wogonin significantly diminished the phosphorylated level of protein kinase B (AKT), and maintenance of low β-catenin expression level was dependent on glycogen synthase kinase 3β (GSK3β) activation at Ser9. Blocking GSK3β/β-catenin pathway was required for wogonin-induced proliferation inhibition and terminal differentiation by using canonical activator lithium chloride (LiCl) and inhibitor dickkopf-1 (Dkk1). Moreover, intravenous administration of wogonin delayed the growth of C6 glioma in the intracranial tumor model. These findings provide the evidence and mechanistic support for wogonin-based differentiation therapies for malignant glioblastoma. Furthermore, inhibition of GSK3β/β-catenin pathway may be a key and requisite factor in glioma differentiation.
    Toxicology Letters 07/2013; · 3.15 Impact Factor
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    ABSTRACT: Natural flavonoids from plants have been demonstrated to possess promising chemopreventive activities against various diseases. 7-{4-[Bis-(2-hydroxy-ethyl)-amino]-butoxy}-5-hydroxy-8-methoxy-2-phenyl-chromen-4-one (V8), a newly synthesized derivative of wogonin may have antioxidant, antiviral, anti-inflammatory and anti-tumor potentials as wogonin. Based on the recent findings of V8, the anti-tumor activities and fundamental mechanisms by which V8 inhibits growth of hepatocellular carcinoma were further investigated in this study. After the treatment of V8, a significant inhibition of HepG2 cell proliferation was observed in a dose-dependent manner with the IC50 value of 23 μM using MTT assay. The exposure to V8 also resulted in apoptosis induction and an accumulation of ROS and Ca(2+). Meanwhile, a release of cytochrome c (Cyt-c), activation of BH-3 only proteins and Bax, decrease in mitochondrial membrane potential ΔΨ, as well as a suppression of Bcl-2, pro-caspase9 and pro-caspase3 expression were shown. Moreover, knocking down CHOP partly decreased the effect of V8-mediated apoptosis and activation of GRP78, p-PERK, p-eIF2α, ATF4 and CHOP modulated ER stress triggered by V8. In vivo, V8 inhibited the transplanted mice H22 liver carcinomas in a dose-dependent manner. Compared with wogonin, V8 exhibited stronger anti-proliferative effects both in vitro and in vivo. The underlying mechanism of activating PERK-eIF2α-ATF4 pathway by which V8 induces apoptosis was verified once again in vivo. The apoptosis induction via the mitochondrial pathway by modulating the ROS-mediated ER signaling pathway might serve to provide support for further studies of V8 as a possible anticancer drug in the clinical treatment of cancer.
    Archives of Toxicology 07/2013; · 5.22 Impact Factor
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    ABSTRACT: Patients with inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, are at a significantly increased risk of developing colorectal cancer, and aberrant interleukin (IL)-6/STAT3 signaling pathway exists in both inflammatory bowel disease and inflammation-related gastrointestinal cancers. We have previously found that oroxylin A inhibited the NF-κB signaling in human colon tumor HCT-116 cells. However, whether oroxylin A could inhibit the colitis-associated carcinogenesis remains to be determined. HCT-116 cells were treated with various concentrations of oroxylin A. Expression of relative proteins of IL-6/STAT3 signaling pathway was assayed by Western blot and immunofluorescence analysis. Mouse model for colitis-associated colorectal cancer was induced by a combined treatment with 10 mg/kg azoxymethane (AOM) followed by 3 cycles of 2.5% dextran sodium sulfate in C57BL/6 mice. IL-6 and IL-1β gene expression were analyzed by quantitative real-time PCR. Expression of relative proteins was examined by immunohistochemistry and Western blot. Oroxylin A effectively inhibited IL-6/STAT3 pathway in human HCT-116 cells, and the effect of oroxylin A was reversible. Dietary administration of oroxylin A throughout the experimental period significantly reduced the tumor burden, inhibited cell proliferation, and induced apoptosis in colon carcinomas. The expression of inflammatory cytokines IL-6 and IL-1β decreased in tumors in oroxylin A-treated mice. The IL-6/STAT3 signaling pathway was attenuated in oroxylin A-treated mice. Our results demonstrated that oroxylin A inhibits colitis-associated carcinogenesis through modulating IL-6/STAT3 pathway in AOM/dextran sodium sulfate mouse model and in HCT-116 cells.
    Inflammatory Bowel Diseases 07/2013; · 5.12 Impact Factor
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    ABSTRACT: Oroxylin A is a naturally occurring monoflavonoid isolated from the root of Scutellaria baicalensis Georgi, which has been used in traditional Chinese medicine for its anti-tumor, anti-inflammatory and anti-bacterial properties. The purpose of this study is to investigate the reversal effect and the fundamental mechanisms of oroxylin A in MCF7/ADR cells. Data indicated that oroxylin A showed strong reversal potency in MCF7/ADR cells and the reversal fold (RF) reached 4.68. After treatment with oroxylin A, MCF7/ADR cells displayed reduced functional activity and expression of MDR1 at both the protein and mRNA levels. Meanwhile, oroxylin A induced cells G2/M arrest in a concentration-dependent manner by increasing the expression of p-Chk2 (Thr68). Moreover, western blot and EMSA assays were used to reveal the inhibition of NF-κB in nucleus and the suppression of NF-κB binding activity by oroxylin A. NSC 109555 ditosylate-Chk2 inhibitor partly dismissed G2/M arrest induced by oroxylin A, reversed the increased trend of p-Chk2 and p-P53 (Ser20), inhibited the decreasing effect of oroxylin A on the expression of P-gp and decreased the reversal fold of 90 μM oroxylin A from 4.68 fold to 1.73 fold. In conclusion, we suggested that oroxylin A reversed MDR by G2/M arrest and the underlying mechanism attributed to the suppression of P-gp expression via Chk2/P53/NF-κB signaling pathway.
    Toxicology Letters 05/2013; 219(2):107–115. · 3.15 Impact Factor
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    ABSTRACT: Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found wogonin decreased the expression of HIF-1α by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1α by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel-Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1α. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1α and promoted its degradation in proteasome. We also found wogonin could inhibit nuclear translocation of HIF-1α. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1α in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1α directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1α and provided a new sight into the mechanisms of wogonin against cancers.
    Toxicology and Applied Pharmacology 05/2013; · 3.98 Impact Factor
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    ABSTRACT: HQS-3 is a newly baicalein derivative with a benzene substitution. We investigated the anticancer effect of HQS-3 in vivo and in vitro. HQS-3 significantly decreased tumor growth in mice inoculated with Heps and HepG2 cells; and had little influence on the state and weight of animals. After treatment with 20 mg/kg HQS-3, the inhibitory rate of tumor weight in mice inoculated with Heps and HepG2 cells were 63.62% and 68.03%, respectively. Meanwhile, HQS-3 inhibited the viability of various kinds of tumor cells with IC50 values in the range of 22.98 to 54.32 μM after 48 h treatment measured by MTT-assay. HQS-3 remarkably inhibited viability of hepatoma cells in a concentration- and time-dependent manner and induced apoptosis in HepG2 cells by DAPI staining and Annexin V/PI double staining. The apoptosis-induction effect of HQS-3 was attributed to its ability to modulate the actvity of caspase-9, caspase-3 and PARP. Moreover, the expression of bax protein was increased while the bcl-2 protein was decreased, leading to an increase in Bax/Bcl-2 ratio. The accumulation of ROS induced by HQS-3 in HepG2 cells was also observed. The further results suggested that HQS-3 induced mitochondrial-mediated apoptosis by increasing ROS level and inhibiting the expression of anti-oxidative protein SOD2. HQS-3 exerted anti-tumor activity both in vitro and in vivo via inducing tumor cells apoptosis, and these results suggested that it deserves further investigation as a novel chemotherapy for human tumors.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 04/2013; · 2.61 Impact Factor
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    ABSTRACT: Metabolic alteration in cancer cells is one of the most conspicuous characteristics that distinguish cancer cells from normal cells. Many studies suggest that several underlying mechanisms lead to the Warburg effect (increased aerobic glycolysis) during cancer development. Here, we explored how oroxylin A affected the glycolytic metabolism in cancer cells and the underlying mechanism involved in this process. Our data revealed that both oroxylin A and adriamycin could inhibit lactate generation and glucose uptake in HepG2 cells at mild concentrations, without causing robust cell apoptosis. Oroxylin A has exerted little influence on the oxygen consumption, whereas adriamycin decreased oxygen consumption in a concentration-dependent manner. Moreover, oroxylin A could increase protein and mRNA expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome c oxidase 2 (SCO2), which are the key metabolic modulators regulated by p53. Meanwhile adriamycin could increase protein and mRNA expression of TIGAR and SCO2, but decrease that of phosphoglycerate mutase (PGM). Oroxylin A and adriamycin also modulated the stability and activity of p53 through inducing phosphorylation of p53 at Ser15 and suppressing the expression of MDM2. Furthermore, p53 siRNA and p53 inhibitor assay in wild-type p53 HepG2 cells both revealed the key role of p53 in oroxylin A and adriamycin-mediated glycolytic metabolism regulation. Transfecting wt p53 plasmid to p53-deficient H11299 cells could inverse some of the metabolic characteristics regulated by oroxylin A. This study revealed a new aspect of glucose metabolism regulation of oroxylin A, which may contribute to its new anticancer mechanism.
    The international journal of biochemistry & cell biology 04/2013; · 4.89 Impact Factor

Publication Stats

592 Citations
306.66 Total Impact Points


  • 2007–2013
    • China Pharmaceutical University
      • • Jiangsu Key Laboratory of Carcinogenesis and Intervention
      • • School of Life Science and Technology
      • • Department of Physiology
      Nan-ching-hsü, Jiangxi Sheng, China