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ABSTRACT: Chronic inflammation-promoted metastasis has been considered as a major challenge in cancer therapy. Pro-inflammatory cytokine TNFα can induce cancer invasion and metastasis associated with epithelial-mesenchymal transition (EMT). However, the underlying mechanisms are not entirely clear. In this study, we showed that TNFα induces EMT in human HCT116 cells and thereby promotes colorectal cancer (CRC) invasion and metastasis. TNFα-induced EMT was characterized by acquiring mesenchymal spindle-like morphology and increasing the expression of N-cadherin and fibronectin with a concomitant decrease of E-cadherin and Zona occludin-1(ZO-1). TNFα treatment also increased the expression of transcription factor Snail, but not Slug, ZEB1 and Twist. Overexpression of Snail induced a switch from E-cadherin to N-cadherin expression in HCT116 cells, which is a characteristic of EMT. Conversely, knockdown of Snail significantly attenuated TNFα-induced EMT in HCT116 cells, suggesting that Snail plays a crucial role in TNFα-induced EMT. Interestingly, exposure to TNFα rapidly increased Snail protein expression and Snail nuclear localization but not mRNA level upregulation. Finally, we demonstrated that TNFα elevated Snail stability by activating AKT pathway and subsequently repressing GSK-3β activity and decreasing the association of Snail with GSK-3β. Knockdown of GSK-3β further verified our finding. Taken together, these results revealed that AKT/GSK-3β-mediated stabilization of Snail is required for TNFα-induced EMT in CRC cells. Our study provides a better understanding of inflammation-induced CRC metastasis.
PLoS ONE 01/2013; 8(2):e56664. · 4.09 Impact Factor
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ABSTRACT: Curcumin (diferuloylmethane) is a polyphenol natural product of the plant Curcuma longa, and has a diversity of antitumor activities. T63, a new 4-Arylidene curcumin analogue, was reported to inhibit proliferation of lung cancer cells. However, its precise molecular anti-tumor mechanisms have not been well elucidated. Here, we showed that T63 could significantly inhibit the proliferation of A549 and H460 human lung cell lines via induction of G0/G1 cell cycle arrest and apoptosis. We found that reactive oxygen species (ROS)-activated FOXO3a cascade plays a central role in T63-induced cell proliferation inhibition. Mechanistically, enhancement of ROS production by T63 induced FOXO3a expression and nuclear translocation through activation of p38MAPK and inhibition of AKT, subsequent elevated the expression of FOXO3a target genes, including p21, p27 and Bim, then increased the levels of activated caspase-3 and decreased the levels of cyclin D1. Moreover, antioxidant N-acetyl cysteine markedly blocked the above effects, and small interfering RNA-mediated knock down of FOXO3a also significantly decreased T63-induced cell cycle arrest and apoptosis. In vivo experiment showed that T63 significantly suppressed the growth of A549 lung cancer xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. These data indicated that the novel curcumin analogue T63 is a potent antitumor agent that induces cell cycle arrest and apoptosis, and has significant therapeutic potential for lung cancer.
Free radical biology & medicine 10/2012; · 5.42 Impact Factor
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ABSTRACT: A series of 3-nitrochromenes were designed and synthesized. These compounds showed good inhibitory activity against thioredoxin reductase (TrxR) and the proliferation of A549 cancer cells. The structure-activity relationship analysis indicates that the 3-nitrochromene scaffold is the crucial pharmacophore for achieving good inhibitory activity. The bromo-substitutions at the 6- and 8-position of 3-nitrochromene significantly increase the inhibitory activity.
Archiv der Pharmazie 07/2012; 345(10):767-70. · 1.71 Impact Factor
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ABSTRACT: Indolamine2, 3-dioxygenase (IDO) is expressed in tumor antigen presenting cells (APCs) and plays an important role in tumor immune tolerance. Inhibiting its activity may break tumor immune tolerance and thus promote therapeutic effects. Thus, a specific inhibitor of IDO, 1-methyl-tryptophan (1-MT), is being used more and more frequently in anti-tumor studies. However, IDO also maintains systemic immune balance by suppressing abnormal immune responses. Therefore, targeting IDO in tumor-associated APCs in a way that does not disrupt immune balance warrants further investigation. In this study, we developed a new tumor vaccine, FAPτ-MT, which was produced by conjugating 1-MT to a tumor associated antigen, fibroblast activation protein α (FAPα). The results in vitro confirmed that 1-MT could be dissociated from the FAPτ-MT vaccine and inhibit intracellular IDO activity. In an FAPα-positive tumor model, the FAPτ-MT vaccine elicited an anti-tumor response which was similar to systemic treatment with the FAPτ vaccine plus 1-MT. Most importantly, administration of the FAPτ-MT vaccine did not lead to pregnancy failiure in mice carrying allogeneic fetuses. These findings that FAPτ-MT breaks tumor immune tolerance as a local IDO inhibitor, suggest that conjugation of 1-MT to a tumor antigen peptide is a potentially effective clinical cancer immunotherapy.
Cancer biology & therapy 05/2011; 11(10):866-73. · 2.64 Impact Factor
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ABSTRACT: The clinical outcomes of most immunotherapeutic strategies have been less effective than anticipated partially because of the tumor immune tolerance induced by many immune tolerance factors, which originate from the tumor and tumor microenvironment. Indoleamine 2, 3-dioxygenase (IDO) is an interferon-γ (IFN-γ)-inducible enzyme and is one of main immune tolerance factors during tumor development. Sodium butyrate (NaB) has received much attention as a potential chemopreventive agent for cancer treatment due to its protective action against intracellular events including IFN-γ-mediated signaling transduction. Therefore, the question remains whether IDO is a target of the anti-tumor action of NaB. In this study, we demonstrate for the first time that NaB down-regulated IDO via both transcriptional and post-transcriptional mechanisms. NaB repressed the activity of STAT1 to inhibit STAT1-driven transcriptional activity of IDO. These mechanisms included inhibiting STAT1 701 tyrosine phosphorylation, nuclear translocation, and repression of STAT1 binding to γ-activated sites (GAS). Moreover, immunoprecipitation and immunoblotting assays showed that treatment of cells with NaB caused dramatic ubiquitination of total intracellular proteins, including IDO. Blocking 26S proteasome activity by addition of its specific inhibitor, bortezomib, reversed the ubiquitination and down-regulation of IDO. These results suggest that NaB-induced STAT1 activity inhibition and ubiquitin/proteasome-dependent proteolysis are involved in the down-regulation of IDO. The discoveries in this study represent a new mechanism in the anti-tumor action of NaB and may have implications for development of clinical cancer immunotherapy.
The international journal of biochemistry & cell biology 11/2010; 42(11):1840-6. · 4.89 Impact Factor
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ABSTRACT: A series of new natural tanshinone-like oxoheterocyclic-fused ortho-quinone derivatives were synthesized from readily available benzofuranol and N-substituted dienes via IBX oxidation-cycloaddition-aromatization procedure. The regiospecific Diels-Alder cycloaddition reactions of N-dienes were achieved efficiently with a variety of dienophiles. It is found that the amide moiety in the molecular could be preserved or eliminated by control of the aromatization conditions. Selected oxoheterocyclic-fused ortho-quinones as well as several thioheterocyclic-fused ortho-quinones we obtained before were evaluated for their cytotoxicities on different cancer cell lines and the Structure-Activity Relationship (SAR) was discussed.
European journal of medicinal chemistry 05/2009; 44(10):3915-21. · 3.27 Impact Factor
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Yu-Jing Lu,
Tian-Miao Ou,
Jia-Heng Tan,
Jin-Qiang Hou,
Wei-Yan Shao,
Dan Peng,
Ning Sun,
Xiao-Dong Wang,
Wei-Bin Wu, Xian-Zhang Bu,
Zhi-Shu Huang,
Dik-Lung Ma,
Kwok-Yin Wong,
Lian-Quan Gu
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ABSTRACT: A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies. Introduction of a positive charge not only significantly improved the binding ability but also induced the selectivity toward antiparallel quadruplex, whereas the nonmethylated derivatives tended to stabilize hybrid-type quadruplexes. NMR and molecular modeling studies revealed that the ligands stacked on the external G-quartets and the positively charged 5- N atom could contribute to the stabilizing ability. Long-term exposure of human cancer cells to 2r showed a remarkable cessation in population growth and cellular senescence phenotype and accompanied by a shortening of the telomere length.
Journal of Medicinal Chemistry 10/2008; 51(20):6381-92. · 4.80 Impact Factor
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Xu Qiu,
Zhong Liu,
Wei-Yan Shao,
Xing Liu,
Da-Ping Jing,
Yan-Jun Yu,
Lin-Kun An,
Shi-Liang Huang, Xian-Zhang Bu,
Zhi-Shu Huang,
Lian-Quan Gu
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ABSTRACT: Series of curcumin derivatives were synthesized; the inhibitory activities on thioredoxin reductase (TrxR) of all analogues were evaluated by DTNB assay in vitro. It is found that most of the analogues can inhibit TrxR in the low micromolar range; Structure-activity relationship analysis reveals that analogues with furan moiety have excellent inhibitory effect on TrxR in an irreversible manner, indicating that the furan moiety may serve as a possible pharmacophore during the interaction of curcumin analogues with TrxR. The effect of selected curcuminoids on growth of different TrxR overexpressed cancer cell lines was also investigated and discussed.
Bioorganic & medicinal chemistry 10/2008; 16(17):8035-41. · 2.82 Impact Factor
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ABSTRACT: A series of indolizinoquinoline-5,12-dione derivatives (IQDs) are synthesized and evaluated for their cytotoxic activities toward human lung adenocarcinoma (GLC-82), large-cell lung carcinoma (NCI-H460), promyelocytic leukemia (HL-60) and breast carcinoma (MCF-7) cells by MTT method. Most of the IQDs show significant cytotoxic potency. In addition, the evaluation of structure-activity relationships indicated that the incorporation of electron-withdrawing substituents at the C or D ring will enhance the activities of the target compounds distinctly. The topoisomerase I inhibitory activity is also measured.
Bioorganic & medicinal chemistry 05/2008; 16(8):4617-25. · 2.82 Impact Factor
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ABSTRACT: In order to better understand the molecular aspects of the cytotoxic action mechanisms, the cytotoxicity of alkannin derivatives, 1-10, on five human tumor cell lines were examined and their standard redox potentials in aprotic medium were tested by means of cyclic voltammetry. It was suggested that the oxidative potential is closely related to the cytotoxicity. The more negative the oxidative potential of the hydroquinones, the higher cytotoxicity of these derivatives. The results of the compounds 5, 7, 9 and 10 with bad leaving groups, have higher cytotoxic action is not agreed with the bioreductive alkylation mechanism of quinones. It indicates that the molecular mechanism involving cytotoxicity of alkannin derivatives may favor the mechanism of production of reactive oxygen.
European Journal of Medicinal Chemistry 01/2006; 40(12):1341-5. · 3.35 Impact Factor
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Shi‐Liang Huang,
Yi Luo,
Zhi‐Shu Huang,
Xing‐Yuan Wang, Xian‐Zhang Bu,
Pei‐Qing Liu,
Lin Ma,
Bing‐Fen Xie,
Zong‐Chao Liu,
Yue‐Ming Li,
Albert S. C. Chan
Synthetic Communications 01/2006; 36(18):2667-2684. · 1.06 Impact Factor
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Jin-Lin Zhou,
Yu-Jing Lu,
Tian-Miao Ou,
Jun-Min Zhou,
Zhi-Shu Huang,
Xiao-Feng Zhu,
Cui-Juan Du, Xian-Zhang Bu,
Lin Ma,
Lian-Quan Gu,
Yue-Ming Li,
Albert Sun-Chi Chan
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ABSTRACT: A new series of quindoline derivatives (4a-j) were designed and synthesized to develop novel and potent telomerase inhibitors. The interaction of the G-quadruplex of human telomere DNA with these newly designed molecules was examined via circular dichroism spectroscopy and electrophoretic mobility shift assay (EMSA). The selectivity between the quindoline derivative (4a) and G-quadruplex or duplex DNA was investigated by competition dialysis. These new compounds as inhibitors of telomerase were also investigated through the utilization of modified telomerase repeat amplification protocol (TRAP) assay. The results revealed that the introduction of electron-donating groups such as substituted amino groups at the C-11 position of quindoline significantly improved the inhibitory effect on telomerase activity ((Tel)IC50 > 138 microM for quindoline, 0.44-12.3 microM for quindoline derivatives 4a-j). The quindoline derivatives not only stabilized the G-quadruplex structure but also induced the G-rich telomeric repeated DNA sequence to fold into quadruplex.
Journal of Medicinal Chemistry 12/2005; 48(23):7315-21. · 5.25 Impact Factor
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ABSTRACT: [reaction: see text] A unique reaction of 4-hydroxycoumarins with p-benzoquinone and pyridine was found, and through the reaction, six zwitterionic 4-hydroxycoumarin derivatives were synthesized. The structures of these compounds were determined by IR, MS(ESI), 1H NMR, 13C NMR, and single-crystal X-ray diffraction studies.
Organic Letters 01/2005; 6(26):4853-5. · 5.86 Impact Factor
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ABSTRACT: A good strategy was brought forward for designing efficient haptens and complete antigens for 3-amino-2-oxazolidinone (AOZ). Haptens designed newly were achieved facilely in good yield by using LiCl–N(Et)3 as new catalysis system, the structure of which was elucidated by spectroscopy analysis, such as NMR and MS. Novel antigens for AOZ were prepared successfully by convenient active ester method. The ratios of haptens 3 and 4 to carrier proteins were proven respectively as 41:1 (5a), 39:1 (6a), 11:1 (5b) and 9:1 (6b) by trinitrobenzene sulfonic acid (TNBS) method. The results of indirect competitive ELISA (ic-ELISA) of antiserums indicated that the haptens with a short unsaturated side chain can evoke specific immune response effectively.
Chinese Chemical Letters 18(12):1490-1492. · 0.98 Impact Factor
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Tetrahedron Letters 47(24):4085-4089. · 2.68 Impact Factor
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Tetrahedron Letters 46(30):5085-5088. · 2.68 Impact Factor
