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Jingkao Chen,
Ying Ouyang,
Lin Cao,
Wenbo Zhu,
Yuxi Zhou,
Yuehan Zhou,
Haipeng Zhang,
Xiaoxiao Yang,
Lifang Mao,
Suizhen Lin,
Jun Lin,
Jun Hu, Guangmei Yan
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ABSTRACT: BACKGROUND:: Glioblastoma (GBM), the most common primary brain tumor, is the most aggressive malignancy in humans. Its rapid proliferation is a major obstacle to successful treatment. Patients with GBM often suffer from psychological disturbances associated with poor prognosis and physical discomfort. Diazepam is one of the most frequently used benzodiazepines (BZs) in cancer patients for its desirable psychotropic effects. The central effects of BZs are mediated by the activation of central BZ receptors. This study investigates whether diazepam has inhibitory effect on proliferation of GBM cell line T98G and explores its possible mechanism. METHODS:: Cell viability and proliferation were respectively determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay. Cell cycle distribution was examined by flow cytometry. Western blot with specific protein antibodies was used to detect regulatory proteins involved in cell cycle regulation. RESULTS:: Diazepam significantly decreased the proliferation of T98G cells in a dose-dependent and time-dependent manner. This effect was not reversed by the central BZ receptor antagonist flumazenil or the peripheral BZ receptor antagonist PK11195, indicating that it was not mediated by BZ receptors. Flow cytometry indicated that diazepam caused a cell accumulation in G0/G1 phase, thereby contributing to cell proliferation inhibition. Furthermore, our findings showed that lessened phosphorylation of Rb accounted for diazepam-induced G0/G1 phase arrest. CONCLUSION:: Diazepam inhibits the proliferation of human GBM T98G cells by inducing G0/G1 phase arrest. Diazepam has potential to be a lead for new drugs in GBM therapy because of its antitumor activity.
Journal of neurosurgical anesthesiology 03/2013; · 2.41 Impact Factor
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Yunling Dou,
Yuan Li,
Jingkao Chen,
Sihan Wu,
Xiao Xiao,
Shanshan Xie,
Lipeng Tang,
Min Yan,
Youqiong Wang,
Jun Lin,
Wenbo Zhu, Guangmei Yan
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ABSTRACT: Transient receptor potential melastatin 7 (TRPM7), a Ca(2+)-permeable channel, has been demonstrated to be present in cancer cells and involved in their growth and proliferation. The present study used midazolam, a benzodiazepine class anesthesic, to pharmacologically intervene in the expression of TRPM7 and to inhibit cancer cell proliferation. Midazolam significantly inhibited the growth and proliferation of FaDu human hypopharyngeal squamous cell carcinoma cells, concurring with the induction of G(0)/G(1) cell cycle arrest and blockage of Rb activation. Central-type and peripheral-type benzodiazepine receptor antagonists did not abrogate proliferation inhibition by midazolam, while the specific TRPM7 agonist bradykinin reversed this effect. In addition, other benzodiazepines, diazepam and clonazepam also exhibited anti-proliferative activities. The inhibitory activity on cancer cell growth and proliferation, combined with the TRPM-dependent mechanism, reveals the anticancer potential of midazolam as a TRPM7 inhibitor and supports the suggestion that TRPM7 is a valuable target for pharmaceutical intervention.
Oncology letters 03/2013; 5(3):1010-1016. · 0.11 Impact Factor
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ABSTRACT: Tumor invasion and migration are major causes of mortality in patients with cervical carcinoma. Tumors under hypoxic conditions are more invasive and have a higher metastasic activity. Lysyl oxidase (LOX) is a hypoxia-responsive gene. LOX has been shown to be essential for hypoxia-induced metastasis in breast cancer. However, the direct impact of LOX on cervical cancer cell motility remains poorly understood. Our study revealed that LOX expression at protein and catalytic levels is upregulated in cervical cancer cells upon exposure to hypoxia. Hypoxia induced mesenchymal-like morphological changes in HeLa and SiHa cells which were accompanied by upregulation of α-SMA and vimentin, two mesenchymal markers, and downregulation of E-cadherin, an epithelial marker, indicating the epithelial-mesenchymal transition (EMT) of cervical cancer cells occurred under hypoxic conditions. Treatment of tumor cells with β-aminopropionitrile (BAPN), an active site inhibitor of LOX, blocked the hypoxia-induced EMT morphological and marker protein changes, and inhibited invasion and migration capacities of cervical carcinoma cells in vitro. Collectively, these findings suggest LOX enhances hypoxia-induced invasion and migration in cervical cancer cells mediated by the EMT which can be inhibited by BAPN.
Oncology Reports 11/2012; · 1.84 Impact Factor
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ABSTRACT: We aim to pharmacologically downregulate heat shock protein 27 (HSP27) through triptolide (TPL) to improve the drug sensitivity of pancreatic cancer to cisplatin (DDP).
In vitro, we assessed cell viability and apoptosis by the combination of TPL and DDP in gemcitabine-resistant human pancreatic carcinoma PANC-1 and MIA PaCa-2 cell lines and examined the effect of silencing HSP27 by a small interfering RNA on cytotoxicity induced by TPL or DDP. In vivo, we apply TPL with DDP in a xenograft model to test the synergic action.
Triptolide cooperates with DDP to decrease cell viability and to induce apoptosis via the mitochondrial pathway, which is accompanied by a sharp decline in HSP27. Knocking down endogenous HSP27 can sensitize cancer cells to cytotoxicity with TPL or DDP, indicating the critical role of HSP27 down-regulation in the synergic effect. Meanwhile, TPL acts in synergy with DDP to cause tumor regression in vivo.
The combined therapy of TPL and DDP triggers a synergic apoptosis via inhibiting HSP27 in human gemcitabine-resistant pancreatic carcinoma and has a strong potential to be developed into a new effective regimen for pancreatic cancer treatment.
Pancreas 05/2012; 41(7):1029-38. · 2.39 Impact Factor
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Haipeng Zhang,
Wenbo Zhu,
Xingwen Su,
Sihan Wu,
Yuan Lin,
Jingjie Li,
Youqiong Wang,
Jingkao Chen,
Yuxi Zhou,
Pengxin Qiu, Guangmei Yan,
Shujin Zhao,
Jun Hu,
Jingxia Zhang
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ABSTRACT: Malignant glioma is the most devastating and aggressive tumor in brain, characterized by rapid proliferation and diffuse invasion. Chemotherapy and radiotherapy are the pivotal strategies after surgery; however, high drug resistance of malignant glioma and the blood-brain barrier usually render chemotherapy drugs ineffective. Here, we find that triptolide, a small molecule with high lipid solubility, is capable of inhibiting proliferation and invasion of malignant glioma cells effectively. In both investigated malignant glioma cell lines, triptolide repressed cell proliferation via inducing cell cycle arrest in G0/G1 phase, associated with downregulation of G0/G1 cell cycle regulators cyclin D1, CDK4, and CDK6 followed by reduced phosphorylation of retinoblastoma protein (Rb). In addition, triptolide induced morphological change of C6 cells through downregulation of protein expression of MAP-2 and inhibition of activities of GTPases Cdc42 and Rac1/2/3, thus significantly suppressing migratory and invasive capacity. Moreover, in an in vivo tumor model, triptolide delayed growth of malignant glioma xenografts. These findings suggest an important inhibitory action of triptolide on proliferation and invasion of malignant glioma, and encourage triptolide as a candidate for glioma therapy.
Journal of Neuro-Oncology 05/2012; 109(1):53-62. · 3.21 Impact Factor
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ABSTRACT: Glioma is the most common malignant cancer affecting the central nerve system, with dismal prognosis. Differentiation-inducing therapy is a novel strategy that has been preliminarily proved effective against malignant glioma. We have reported previously that activation of cAMP/protein kinase A (PKA) pathway is capable of inducing glioma cell differentiation, characterized by astrocyte-like shape and dramatic induction of astrocyte biomarker glial fibrillary acidic protein (GFAP). However, little progress has been made on molecular mechanisms related. Here we demonstrate that microRNA 335 (miR-335) is responsible for the glioma cell differentiation stimulated by activation of cAMP/PKA pathway. In the cAMP elevator cholera toxin-induced differentiation model of rat C6 glioma cells, miR-335 was significantly up-regulated, which was mimicked by other typical cAMP/PKA pathway activators (e.g., forskolin, dibutyryl-cAMP) and abolished by PKA-specific inhibitor (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i] [1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720). In an assay measuring gain and loss of miR-335 function, exogenetic miR-335 resulted in induction of GFAP, whereas miR-335 specific inhibitor antagomir-335 violently blocked cholera toxin-induced GFAP up-regulation. It is noteworthy that in human U87-MG glioma cells and human primary culture glioma cells, miR-335 also mediated cholera toxin-induced differentiation. Taken together, our findings suggest that miR-335 is potently required for differentiation of malignant glioma cells induced by cAMP/PKA pathway activation, and a single microRNA may act as an important fate determinant to control the differentiation status of malignant gliomas, which has provided a new insight into differentiation-inducing therapy against malignant gliomas.
Molecular pharmacology 12/2011; 81(3):292-8. · 4.53 Impact Factor
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Guangmei Yan,
Guojie Zhang,
Xiaodong Fang,
Yanfeng Zhang,
Cai Li,
Fei Ling,
David N Cooper,
Qiye Li,
Yan Li,
Alain J van Gool, [......],
Xiuqing Zhang,
Yingrui Li,
Wen Wang,
Michael G Katze,
Bing Su,
Rasmus Nielsen,
Huanming Yang,
Jun Wang,
Xiaoning Wang,
Jian Wang
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ABSTRACT: The nonhuman primates most commonly used in medical research are from the genus Macaca. To better understand the genetic differences between these animal models, we present high-quality draft genome sequences from two macaque species, the cynomolgus/crab-eating macaque and the Chinese rhesus macaque. Comparison with the previously sequenced Indian rhesus macaque reveals that all three macaques maintain abundant genetic heterogeneity, including millions of single-nucleotide substitutions and many insertions, deletions and gross chromosomal rearrangements. By assessing genetic regions with reduced variability, we identify genes in each macaque species that may have experienced positive selection. Genetic divergence patterns suggest that the cynomolgus macaque genome has been shaped by introgression after hybridization with the Chinese rhesus macaque. Macaque genes display a high degree of sequence similarity with human disease gene orthologs and drug targets. However, we identify several putatively dysfunctional genetic differences between the three macaque species, which may explain functional differences between them previously observed in clinical studies.
Nature Biotechnology 11/2011; 29(11):1019-23. · 29.50 Impact Factor
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08/2011; , ISBN: 978-953-307-588-4
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Minfeng Shu,
Xiaoke Zheng,
Sihan Wu,
Huimin Lu,
Tiandong Leng,
Wenbo Zhu,
Yuehan Zhou,
Yanqiu Ou,
Xi Lin,
Yuan Lin,
Dong Xu,
Yuxi Zhou, Guangmei Yan
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ABSTRACT: Astrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated.
We report that miR-335 acts as a tumor promoter in conferring tumorigenic features such as growth and invasion on malignant astrocytoma. The miR-335 level is highly elevated in C6 astrocytoma cells and human malignant astrocytomas. Ectopic expression of miR-335 in C6 cells dramatically enhances cell viability, colony-forming ability and invasiveness. Conversely, delivery of antagonist specific for miR-335 (antagomir-335) to C6 cells results in growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenografts. Further investigation reveals that miR-335 targets disheveled-associated activator of morphogenesis 1(Daam1) at posttranscriptional level. Moreover, silencing of endogenous Daam1 (siDaam1) could mimic the oncogenic effects of miR-335 and reverse the growth arrest, proapoptotic and invasion repression effects induced by antagomir-335. Notably, the oncogenic effects of miR-335 and siDAAM1 together with anti-tumor effects of antagomir-335 are also confirmed in human astrocytoma U87-MG cells.
These findings suggest an oncogenic role of miR-335 and shed new lights on the therapy of malignant astrocytomas by targeting miR-335.
Molecular Cancer 05/2011; 10:59. · 3.99 Impact Factor
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ABSTRACT: Malignant gliomas are the most common and lethal intracranial tumors, and differentiation therapy shows great potential to be a promising candidate for their treatment. Here, we have elaborated that a PKA activator, forskolin, represses cell growth via cell cycle arrest in the G0/G1 phase and induces cell differentiation characteristic with elongated processes and restoration of GFAP expression. In mechanisms, we verified that forskolin significantly diminishes the mRNA and protein level of a key cell cycle regulator cyclin D1, and maintenance of low cyclin D1 expression level was required for forskolin-induced proliferation inhibition and differentiation by gain and loss of function approaches. In addition, that forskolin down-regulated the cyclin D1 by proteolytic (post-transcriptional) mechanisms was dependent on GSK-3β activation at Ser9. The pro-differentiation activity of forskolin and related molecular mechanisms imply that forskolin can be developed into a candidate for the future in differentiation therapy of glioma, and cyclin D1 is a promising target for pro-differentiation strategy.
Journal of Cellular Biochemistry 04/2011; 112(9):2241-9. · 2.87 Impact Factor
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ABSTRACT: Differentiation-inducing therapy has been proposed to be a novel potential approach to treat malignant gliomas. Glial fibrillary acidic protein (GFAP) is a well-known specific astrocyte biomarker and acts as a tumor suppressor gene (TSG) in glioma pathogenesis. Previously we reported that a traditional biotoxin cholera toxin could induce malignant glioma cell differentiation characterized by morphologic changes and dramatic GFAP expression. However, the molecular mechanisms underlying GFAP induction are still largely unknown. Here we demonstrate that an oncogenic pathway interleukin-6/janus kinase-2/signal transducer and activator of transcription 3 (IL-6/JAK2/STAT3) cascade mediates the cholera toxin-induced GFAP expression. Cholera toxin dramatically stimulated GFAP expression at the transcriptional level in C6 glioma cells. Meanwhile, phosphorylation of STAT3 and JAK2 was highly induced in a time-dependent manner after cholera toxin incubation, whereas no changes of STAT3 and JAK2 were observed. Furthermore, the IL-6 gene was quickly induced by cholera toxin and subsequent IL-6 protein secretion was stimulated. Importantly, exogenous recombinant rat IL-6 can also induce phosphorylation of STAT3 concomitant with GFAP expression while JAK2 specific inhibitor AG490 could effectively block both cholera toxin- and IL-6-induced GFAP expression. Given that the methylation of the STAT3 binding element can suppress GFAP expression, we detected the methylation status of the critical recognition sequence of STAT3 in the promoter of GFAP gene (-1518 ∼ -1510) and found that it was unmethylated in C6 glioma cells. In addition, neither DNA methyltransferase1 (DNMT1) inhibitor 5-Aza-2'-deoxycytidine (5-AZa-CdR) nor silencing DNMT1 can stimulate GFAP expression, indicating that the loss of GFAP expression in C6 cells is not caused by its promoter hypermethylation. Taken together, our findings suggest that activation of a pro-survival IL-6/JAK2/STAT3 cascade contributes to cholera toxin-induced GFAP expression, which implies that a survival-promoting signal may also play a differentiation-supporting role in malignant gliomas.
Molecular oncology 03/2011; 5(3):265-72. · 4.10 Impact Factor
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ABSTRACT: Renal cell carcinoma (RCC) is the most frequent type of renal-originated malignancy. Although nephrectomy is successfully used to save the lives of patients with localized RCC, treatment of advanced and other refractory RCCs is poor and still inadequate. Here, we show that triptolide, a small molecule and a well-known anti-inflammatory and anti-immunity agent used in the clinic, is capable of inducing cell apoptosis via the mitochondrial pathway in the 786-0 RCC cell line. This induction occurred in concert with reduced expression of genes related to the stabilization of mitochondria such as Bcl-2 and Bcl-XL. Cell cycle analysis showed that exposure to triptolide decreased the proportion of cells in the G0/G1 and G2/M phases, and increased the proportion of cells in the S phase. Cell accumulation in the S phase can be attributed to reduced expression of cell cycle checkpoint regulators such as cyclin A, cyclin B, CDK1, CDK2 and retinoblastoma proteins (Rb). These results raise the possibility that triptolide-induced apoptosis is mediated by cell cycle arrest. Similarly, in another human RCC cell line, OS-RC-2, triptolide-induced apoptosis and cell accumulation in S phase were also observed. Therefore, triptolide emerges as a stimulator of apoptosis by influencing coordinate regulation of proliferation and apoptosis, and may be applicable to the treatment of human renal cell carcinoma.
Oncology Reports 01/2011; 25(4):979-87. · 1.84 Impact Factor
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Nature Biotechnology 01/2011; · 29.50 Impact Factor
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ABSTRACT: Angiotensin-(1-7) displays antihypertensive and antiproliferative properties although its effect on cardiac remodeling and hypertrophy in hypertension has not been fully elucidated. The present study was designed to examine the effect of chronic angiotensin-(1-7) treatment on myocardial remodeling, cardiac hypertrophy and underlying mechanisms in spontaneous hypertension. Adult male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with or without angiotensin-(1-7) or the angiotensin-(1-7) antagonist A-779 for 24 weeks. Mean arterial pressure, left ventricular geometry, expression of the hypertrophic markers ANP and β-MHC, collagen contents (type I and III), collagenase (MMP-1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of MMPs-1 (TIMP-1) were evaluated in WKY and SHR rats with or without treatment. Our data revealed that chronic angiotensin-(1-7) treatment significantly suppressed hypertension, left ventricular hypertrophy, expression of ANP and β-MHC as well as myocardial fibrosis in SHR rats, the effects of which were nullified by the angiotensin-(1-7) receptor antagonist A-779. In addition, angiotensin-(1-7) treatment significantly counteracted hypertension-induced changes in the mRNA expression of MMP-2 and TIMP-1 and collagenase activity, the effects of which were blunted by A-779. In vitro study revealed that angiotensin-(1-7) directly increased the activity of MMP-2 and MMP-9 while decreasing the content of TIMP-1 and TIMP-2. Taken together, our results revealed a protective effect of angiotensin-(1-7) against cardiac hypertrophy and collagen deposition, which may be related to concerted changes in MMPs and TIMPs levels. These data indicated the therapeutic potential of angiotensin-(1-7) in spontaneous hypertension-induced cardiac remodeling.
Toxicology Letters 11/2010; 199(2):173-81. · 3.23 Impact Factor
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ABSTRACT: Severe acute pancreatitis (SAP) remains a challenging disease to manage, with high mortality, limited understanding of pathogenesis and lack of specific therapy. Recombinant fibrinogenase II (rFII) from Agkistrodon acutus venom has been found to degrade tumor necrosis factor-alpha (TNF-α) which is vital in mortality of SAP. Here we investigate the in vivo effects of rFII in rat SAP and confirm the degradation effect of rFII for TNF-αin vitro. The SAP model was prepared by retrograde infusion of 5% sodium taurocholate into the biliopancreatic duct in male Sprague-Dawley rats. Treatment with 1 mg/kg rFII could significantly increase survival rate of SAP rats (P = 0.006) as well as 8 mg/kg Infliximab treatment did. The pancreatic and pulmonary injury and the peritoneal and systemic inflammatory response were also attenuated by rFII as well as Infliximab. Furthermore, rFII inhibited TNF-α secretion by rat peritoneal macrophages in a time- and concentration-dependent manner but didn't influence interleukin (IL) -1β secretion in vitro. The degradation potency of rFII for human TNF-α was greater than that for rat TNF-α. Our findings suggest that rFII could have protective effect on taurocholate-induced SAP in rats, mainly depending on direct degradation of TNF-α.
Biochimie 10/2010; 92(10):1354-61. · 3.02 Impact Factor
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ABSTRACT: FIa, a factor X activator, was isolated from the venom of Daboia russellii siamensis (Myanmar) after a series of chromatographic separations. FIa displayed procoagulant activity by shortening plasma recalcification time and converted human factor X (FX) to activated human factor X (FXa) by cleaving the heavy FX chain, possibly at the Arg51-Ile52 peptide. FIa was positive in a glycoprotein staining test, demonstrating that it is a glycoprotein. Optimal temperature and pH values were important for FIa procoagulant activity. Procoagulant activity was maintained above 85% of the initial activity at pH 7.0 approximately 8.0, and showed equally maximum activity at temperatures ranging from 30 to 50 degrees C. In addition, FIa procoagulant activity was completely inhibited by EDTA (5 mM), but not by PMSF (10 mM), suggesting that it is a metalloproteinase.
Archives of Pharmacal Research 07/2010; 33(7):1043-8. · 1.59 Impact Factor
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ABSTRACT: Malignant gliomas are common and aggressive brain tumours in adults. The rapid proliferation and diffuse brain migration are the main obstacles to successful treatment. Here, we show 25(R)-spirostan-3beta,5alpha,6beta,19-tetrol, a polyhydroxy steroid, is capable of suppressing proliferation and migration of C6 malignant glioma cells in a concentration-dependent manner. The compound 25(R)-spirostan-3beta,5alpha,6beta,19-tetrol was synthesised by seven steps starting from diosgenin in 8.55% overall yield. The structures of the synthetic compounds were characterised by infrared (IR), (1)H nuclear magnetic resonance (NMR), (13)C NMR spectra and EA.
Steroids 12/2009; 75(3):224-9. · 2.83 Impact Factor
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ABSTRACT: Triptolide, a traditional anti-inflammatory and anti-immunodepressive agent, has been reported to exert anti-neoplastic activity on several human tumor cell lines. This study investigates the pro-apoptotic function and the functional mechanism of triptolide on anaplastic thyroid carcinoma (ATC) cells. Experiments presented here demonstrated that triptolide had dose-dependent effects on cell viability of human ATC cell line TA-K cells through inducing cell apoptosis. In the molecular level, triptolide did not successfully initiate p53 signaling pathway, but downregulated the nuclear factor kappaB (NF-kappaB) pathway. Our studies suggest that triptolide functions as an effective apoptotic inducer in a p53-independent, but NF-kappaB-dependent mechanism, thus providing a promising agent for tumor types with p53 mutation/deletion.
Oncology Reports 12/2009; 22(6):1397-401. · 1.84 Impact Factor
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ABSTRACT: Aberrant differentiation is a characteristic feature of neoplastic transformation, while hypoxia in solid tumors is believed to be linked to aggressive behavior and poor prognosis. However, the possible relationship between hypoxia and differentiation in malignancies remains poorly defined. Here we show that rat C6 and primary human malignant glioma cells can be induced to differentiate into astrocytes by the well-known adenylate cyclase activator forskolin. However, hypoxia-inducible factor-1alpha expression stimulated by the hypoxia mimetics cobalt chloride or deferoxamine blocks this differentiation and this effectiveness is reversible upon withdrawal of the hypoxia mimetics. Importantly, knockdown of hypoxia inducible factor-1alpha by RNA interference restores the differentiation capabilities of the cells, even in the presence of cobalt chloride, whereas stabilization of hypoxia-inducible factor-1alpha through retarded ubiquitination by von Hippel-Lindau tumor suppressor gene silence abrogates the induced differentiation. Moreover, targeting of HIF-1 using chetomin, a disrupter of HIF-1 binding to its transcriptional co-activator CREB-binding protein (CBP)/p300, abolishes the differentiation-inhibitory effect of hypoxia-inducible factor-1alpha. Administration of chetomin in combination with forskolin significantly suppresses malignant glioma growth in an in vivo xenograft model. Analysis of 95 human glioma tissues revealed an increase of hypoxia-inducible factor-1alpha protein expression with progressing tumor grade. Taken together, these findings suggest a key signal transduction pathway involving hypoxia-inducible factor-1alpha that contributes to a differentiation defect in malignant gliomas and sheds new light on the differentiation therapy of solid tumors by targeting hypoxia-inducible factor-1alpha.
FEBS Journal 11/2009; 276(24):7291-304. · 3.79 Impact Factor
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Wenbo Zhu,
Songmin He,
Yan Li,
Pengxin Qiu,
Minfeng Shu,
Yanqiu Ou,
Yuehan Zhou,
Tiandong Leng,
Jun Xie,
Xiaoke Zheng,
Dong Xu,
Xingwen Su, Guangmei Yan
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ABSTRACT: Triptolide is confirmed to suppress angiogenesis of anaplastic thyroid carcinoma. Here we further expound the precise mechanism involved in this activity. Triptolide downregulated nuclear factor kappa B (NF-kappaB) pathway and its targeting genes associated with endothelial cell mobilization in human umbilical vein endothelial cells (HUVECs) and impaired VEGF expression in thyroid carcinoma TA-K cells. Furthermore, both triptolide and the conditioned medium from triptolide-treated TA-K cells (CMT) significantly attenuated proliferation, migration and tube formation of HUVECs. In vivo, triptolide inhibited TA-K cell-induced tumor growth, vascular formation and VEGF expression. Our data establish that triptolide inhibits tumor angiogenesis by the dual action on vascular endothelial cells and tumor cells, thus providing a novel and overall explanation for the anti-angiogenesis action of triptolide. The multicellular targets emphasize triptolide as a high-performance and potential angiogenesis inhibitor.
Vascular Pharmacology 10/2009; 52(1-2):46-54. · 1.99 Impact Factor
