[Show abstract][Hide abstract] ABSTRACT: The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally-occurring substance, was found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The observable detoxifying/antioxidant genes activation by t-CA, especially heme oxygenase-1 (HO-1), was found to be involved in the cytoprotective effects against carcinogen tert-butylhydroperoxide- and arecoline-elicited oxidative stress and cell injuries. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in the ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2 -mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via the novel p38α/MAPKAPK-2- and PK-N3-dependent signaling. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential in the management of carcinogenesis, and merits for further investigation.
Chemical Research in Toxicology 08/2015; DOI:10.1021/acs.chemrestox.5b00085 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Described herein is the development of a novel series of 7-anilino-indoline-N-benzenesulfonamides, derived from ABT751 (1), as potent anticancer agents. Amongst the synthesized series, compounds 6, 12, 13, and 14 have shown comparable to better anticancer activity on comparing with compound 1. 7-(4-Cyanophenylamino)-1-(4-methoxybenzenesulfonyl)indoline (13) was found to be the most potent one with up to 6 fold better activity against KB, HT29, and MKN45 cancer cell lines with IC50 values of 49.7, 149, and 92nM, respectively. Compound 13 was also found inhibiting multidrug resistant cancer cell lines, blocking cell cycle at G2/M phase, and inhibiting tubulin polymerization. Capillary disruption assay results revealed that compound 13 was able to disrupt formed capillaries in a concentration-dependent manner without affecting cell viability.
[Show abstract][Hide abstract] ABSTRACT: A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 uM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1, 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, Zolinza, N-hydroxy-N'-phenyl-octanediamide) and is therefore seen as a suitable candidate for further investigation.
[Show abstract][Hide abstract] ABSTRACT: 2-Hydroxy-3,4,5-trimethoxybenzophenones (8-16) manifest pseudo-ring formation involving intramolecular hydrogen bonding of the 2-OH and the carbonyl group. Among the synthetic products described in this report, (3-hydroxy-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxyphenyl)-methanone (14) and (3-amino-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxy-phenyl)methanone (16) exhibit significant antiproliferative activity against KB cells with IC 50 values of 11.1 and 11.3 nM, respectively. These two compounds also displayed tubulin affinity comparable to that of combretastatin A-4. In studies with human umbilical vein endothelial cells, compounds 14 and 16 revealed concentration-dependent vascular-disrupting properties. The results support the rationale of the pseudo-ring concept and suggest further investigation of A-ring modification in these benzophenones.
European Journal of Medicinal Chemistry 04/2014; 77:306–314. DOI:10.1016/j.ejmech.2014.02.061 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Investigation of the wood of Cunninghamia konishii resulted in the isolation and characterization of one new abietane diterpenoid, (6α,7β)-7,8-epoxy-6-hydroxyabieta-9(11),13-dien-12-one (1), and two new labdane diterpenoids, (12R)-12-hydroxylabda-8(17),13(16),14-trien-19-oic acid (2) and (12R)-12-hydroxylabda-8(17),13(16),14-trien-18-oic acid (3). The structures of these new compounds were elucidated by analysis of their spectroscopic data.
[Show abstract][Hide abstract] ABSTRACT: Preliminary biological data on 7-anilino-6-azaindoles (8-11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12-22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC50 values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents.
[Show abstract][Hide abstract] ABSTRACT: Oxaliplatin treatment is a mainstay of treatment for advanced gastrointestinal tract cancer, but the underlying mechanisms of acquired oxaliplatin resistance remain largely obscured. We previously demonstrated that increased DNA repair capacity and copper-transporting ATPase 1 (ATP7A) level contributed to oxaliplatin resistance in the human gastric carcinoma cell line TSGH-S3 (S3). In the present study, we applied gene array technology to identify additional resistance factors in S3 cells. We found that interleukin-6 (IL-6), aldo-keto reductase 1C1 (AKR1C1), and AKR1C3 are the top 3 upregulated genes in S3 cells when compared with parent TSGH cells. Despite a higher level of endogenous IL-6 in S3, IL-6 receptor (IR-6R, gp-80, and gp-130) levels were similar between TSGH and S3 cells. The addition of exogenous IL-6, IL-6 targeted siRNA, or neutralizing antibodies neither affected Stat3 activation, a downstream target of IL-6, nor changed oxaliplatin sensitivity in S3 cells. However, manipulation of AKR1C activity with siRNA or AKR1C inhibitors significantly reversed oxaliplatin resistance. AKR1Cs are classical antioxidant response element (ARE) genes that can be transcriptionally upregulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of Nrf2 not only decreased the levels of AKR1C1, AKR1C2, and AKR1C3 mRNA and protein but also reversed oxaliplatin resistance in S3 cells. Taken together, these results suggest that activation of the Nrf2/AKR1C axis may contribute to oxaliplatin resistance in S3 cells but that the IL-6 signaling pathway did not contribute to resistance. Manipulation of Nrf2/AKR1Cs activity may be useful for management of oxaliplatin-refractory gastric cancers.
[Show abstract][Hide abstract] ABSTRACT: Histone deacetylases (HDACs), important epigenetic regulatory enzymes, can reduce cardiac hypertrophy and cardiac fibrosis. However, the mechanisms underlying the antifibrotic activity of HDAC inhibitors remain unclear. The purposes of this study were to evaluate the effects of an HDAC inhibitor on systolic heart failure (HF) and investigate the potential mechanisms.
Echocardiographic, histologic, atrial natriuretic peptide (ANP), and Western blot measurements were performed in HF rats (isoproterenol 100mg/kg, subcutaneous injection) with and without orally administered (100mg/kg for 7 consecutive days) MPT0E014 (a novel HDAC inhibitor). Western blot, migration and proliferation assays were carried out on primary isolated cardiac fibroblasts with and without MPT0E014 (0.1 and 1μM) for 24h.
MPT0E014-treated HF rats (n=6) had better fraction shortening (48±2 vs. 33±4%, p=0.006) and smaller left ventricular end diastolic diameter (4.6±0.2 vs. 5.6±0.3mm, p=0.031) and systolic diameter (2.4±0.2 vs. 3.9±0.3mm, p=0.006) than HF (n=7) rats. MPT0E014-treated HF rats had lower ANP, cardiac fibrosis, and angiotensin II type I receptor (AT1R), transforming growth factor (TGF)-β, and CaMKIIδ protein levels compared to HF rats. MPT0E014 (at 1μM, but not 0.1μM) decreased the migration and proliferation of cardiac fibroblasts. MPT0E014 (0.1 and 1μM) decreased expression of the AT1R and TGF-β.
MPT0E014 improved cardiac contractility and attenuated structural remodeling in isoproterenol-induced dilated cardiomyopathy. The direct antifibrotic activity may have contributed to these beneficial effects.
International journal of cardiology 08/2013; 168(4). DOI:10.1016/j.ijcard.2013.07.111 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In previous research, we found α-enolase to be inversely correlated with progression-free and overall survival in lung cancer patients and detected α-enolase on the surface of lung cancer cells. Based on these findings, we hypothesized that surface α-enolase has a significant role in cancer metastasis and tested this hypothesis in the current study. We found that α-enolase was co-immunoprecipitated with urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen in lung cancer cells and interacted with these proteins in a cell-free dot blotting assay, which can be interrupted by α-enolase-specific antibody. α-Enolase in lung cancer cells co-localized with these proteins and was present at the site of pericellular degradation of extracellular matrix components. Treatment with antibody against α-enolase in vitro suppressed cell-associated plasminogen and matrix metalloproteinase activation, collagen and gelatin degradation, and cell invasion. Examination of the effect of treatment with shRNA plasmids revealed that down regulation of α-enolase decreases extracellular matrix degradation by and the invasion capacity of lung cancer cells. Adoptive transfer of α-enolase-specific antibody to mice resulted in accumulation of antibody in subcutaneous tumor and inhibited the formation of tumor metastasis in lung and bone. This study demonstrated that surface α-enolase promotes extracellular matrix degradation and invasion of cancer cells and that targeting surface α-enolase is a promising approach to suppress tumor metastasis.
PLoS ONE 07/2013; 8(7):e69354. DOI:10.1371/journal.pone.0069354 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microtubule inhibitors have been demonstrated to inhibit hypoxia-inducible factor-1α (HIF-1α expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1α mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-aryl-indoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells including chemoresistant cells with IC50 values ranging from 70 to 150 nM. However, normal cells, such as human umbilical vein endothelial cells (HUVECs), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 510 nM. As similar with typical microtubule inhibitors, MPT0B098 arrests cells in the G2/M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1αprotein, but also destabilizes HIF-1α mRNA. Mechanism of causing unstable of HIF-1α mRNA by MPT0B098 is through decreasing RNA binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1α of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.
Molecular Cancer Therapeutics 04/2013; 12(7). DOI:10.1158/1535-7163.MCT-12-0778 · 5.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heart failure (HF) can increase atrial fibrillation and induce cardiac hypermethylation. Pitx2c plays important roles in the genesis of atrial fibrillation and the promoter region of Pitx2c contains CpG islands. Therefore, epigenetic modification by hypermethylation may reduce Pitx2c expression in atrial myocytes. The purposes of this study were to evaluate whether HF can modulate DNA methylation of Pitx2c and the potential mechanisms. We used real-time PCR, immunoblotting, and pyrosequencing to investigate RNA and protein expressions, and methylation of Pitx2c in isoproterenol-induced HF and healthy rat left atria, and in HL-1 cells with and without (control) the administration of angiotensin II (0.1 and 1 μM) or isoproterenol (1, 10 μM) for 24 h. The HF atrium exhibited increased Pitx2c promoter methylation with increased DNA methyltransferase (DNMT) 1 and decreased Pitx2c proteins compared to the normal atrium. Angiotensin II (0.1 and 1 μM), increased Pitx2c promoter methylation in HL-1 cells with increased DNMT1 and decreased Pitx2c and Kir 2.1 proteins compared to control cells, which were attenuated by the methylation inhibitor, 5-aza-2'-deoxycytidine (DAC, 0.1 μM) or losartan (10 μM, the angiotensin II receptor blocker). However, isoproterenol (1, 10 μM) did not change expressions of Pitx2c, DNMT1 and Kir2.1 proteins. HF induces Pitx2c promoter hypermethylation, and angiotensin II may contribute to the hypermethylation in HF. This article is protected by copyright. All rights reserved.
Clinical and Experimental Pharmacology and Physiology 04/2013; 40(6). DOI:10.1111/1440-1681.12089 · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eburicoic acid (TR1) and dehydroeburicoic acid (TR2), an active ingredient from Antrodia camphorata (AC) solid-state culture was evaluated for the analgesic and anti-inflammatory effects. Treatment with TR1 and TR2 significantly inhibited a numbers of acetic acid-induced writhing response and formalin-induced pain in the late phase. In the anti-inflammatory test, TR1 and TR2 decreased the paw edema at the 4th and 5th h after -carrageenan (Carr) administration, and increased the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the paw edema tissue. We also demonstrated that TR1 and TR2 significantly attenuated the malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β) levels in either edema paw or serum at the 5th h after Carr injection. Western blotting revealed that TR1 and TR2 decreased Carr-induced inducible nitric oxide synthase (iNOS) and cycloxyclase (COX-2) expressions at the 5th h in the paw edema. Treatment with TR1 and TR2 also diminished neutrophil infiltration into the paw edema at the 5th h. The present study suggests that the anti-inflammatory mechanisms of TR1 and TR2 might be related to the decrease of inflammatory cytokines and an increase of antioxidant enzyme activity.
Journal of Agricultural and Food Chemistry 03/2013; 61(21). DOI:10.1021/jf303820k · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Agents that interfere with mitotic progression by disturbing microtubule dynamics are commonly used for cancer treatment. Previously, a series of aroylquinolone regioisomers as novel microtubule inhibitors were discovered. One of these new compounds, MPT0B214 inhibited tubulin polymerization through strongly binding to the tubulin's colchicine-binding site and had cytotoxic activity in a variety of human tumor cell lines. After treatment with MPT0B214, KB cells were arrested in the G2-M phase before cell death occurred, which were associated with upregulation of cyclin B1, dephosphorylation of Cdc2, phosphorylation of Cdc25C and elevated expression of the mitotic marker MPM-2. Furthermore, the compound induced apoptotic cell death through mitochondria/caspase 9-dependent pathway. Notably, several KB-derived multidrug-resistant cancer cell lines were also sensitive to MPT0B214 treatment. These findings showed that MPT0B214 is a potential compound in the treatment of various malignancies.
PLoS ONE 03/2013; 8(3):e58953. DOI:10.1371/journal.pone.0058953 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A variety of functionalities were introduced at 2-aroylquinoline's C5 position, which is considered equivalent to C-3' of the B-ring of CA4, via Suzuki arylation, Sonogashira ethynylation, and Rosenmund-von Braun cyanation. These substitutions are rarely utilized in the modification of 3'-OH of CA4. The resulting products and having cyano and ethynyl groups exhibited comparable antiproliferative and tubulin inhibitory activities to colchicine.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Arginine is a nonessential amino acid which can regulate tumor growth. Argininosuccinate synthetase (ASS) is the rate-limiting enzyme for de novo arginine production. The expression pattern of ASS and the feasibility of arginine deprivation therapy in head and neck cancer have not been investigated.
Materials and methods:
The growth-inhibitory effect of arginine deprivation therapy was assessed either by proliferation assay with head and neck cancer cells cultured in arginine-free medium, or by tetrazolium/formazan dye assay with cells treated with an arginine-depleting drug (arginine deiminase, ADI). The tumor ASS status of 73 oral squamous carcinoma (OSCC) patients was then evaluated immunohistochemically and subsequently correlated with the corresponding clinicopathological parameters.
Head and neck cancer cells cultured in arginine-free medium either completely stopped proliferating, or proliferated minimally. In addition, ADI treatment inhibited the growth of all 8 head and neck cancer cell lines to different degrees. Although cellular ASS level did not correlate well with ADI-sensitivity among these cell lines, knockdown of endogenous ASS potentiated the growth-inhibitory effect of ADI in each individual cell line (FaDu and OEC-M1). In multivariable analysis, high tumor ASS level independently predicted an unfavorable disease-free survival in OSCC patients.
High tumor ASS status is an independent variable predicting a poor disease-free survival in OSCC patients. Arginine deprivation therapy may potentially be used as a new approach to treat head and neck cancer.