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  • Cell Line, Tumor  (164)
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  • 1
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e37764
    Description: Withanolides are a large group of steroidal lactones found in Solanaceae plants that exhibit potential anticancer activities. We have previously demonstrated that a withanolide, tubocapsenolide A, induced cycle arrest and apoptosis in human breast cancer cells, which was associated with the inhibition of heat shock protein 90 (Hsp90). To investigate whether other withanolides are also capable of inhibiting Hsp90 and to analyze the structure-activity relationships, nine withanolides with different structural properties were tested in human breast cancer cells MDA-MB-231 and MCF-7 in the present study. Our data show that the 2,3-unsaturated double bond-containing withanolides inhibited Hsp90 function, as evidenced by selective depletion of Hsp90 client proteins and induction of Hsp70. The inhibitory effect of the withanolides on Hsp90 chaperone activity was further confirmed using in vivo heat shock luciferase activity recovery assays. Importantly, Hsp90 inhibition by the withanolides was correlated with their ability to induce cancer cell death. In addition, the withanolides reduced constitutive NF-κB activation by depleting IκB kinase complex (IKK) through inhibition of Hsp90. In estrogen receptor (ER)-positive MCF-7 cells, the withanolides also reduced the expression of ER, and this may be partly due to Hsp90 inhibition. Taken together, our results suggest that Hsp90 inhibition is a general feature of cytotoxic withanolides and plays an important role in their anticancer activity.
    Keywords: Research Article ; Biology ; Medicine ; Molecular Biology ; Cell Biology ; Oncology ; Biochemistry
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol. 7(5), p. e37897
    Description: In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC50 0.08-1.66 mu g/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a-b and for the carbonyl group of 5-OCOCH3 in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH3), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.
    Keywords: Medical And Health Sciences ; Medicin Och Hälsovetenskap
    ISSN: 1932-6203
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  • 3
    Language: English
    In: Bioorganic & Medicinal Chemistry Letters, 01 July 2016, Vol.26(13), pp.3060-3063
    Description: Chemical investigation on the EtOAc-soluble fraction from the MeOH/DCM extract of a gorgonian sp. afforded two new sterols, 11-acetoxy-24 -methyl-3 ,5 ,6 -trihydroxy-9,11-secocholest-7-en-9-one ( ) and 5 ,6 -epoxy-(22 ,24 )-ergosta-8,22-diene-3 ,7 -diol ( ). The structures of sterols and were elucidated on the basis of spectroscopic analysis and by comparison of their spectroscopic data with those of related analogues. Both and were shown to significantly inhibit the accumulation of the pro-inflammatory iNOS and COX-2 protein in LPS-stimulated RAW264.7 macrophage cells.
    Keywords: Pinnigorgia ; Gorgonian ; Sterol ; Anti-Inflammatory Activity ; Inos ; Cox-2 ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2011, Vol.6(8), p.e23922
    Description: Protoapigenone, a natural flavonoid possessing an unusual p-quinol moiety on its B-ring, is a novel prospective anticancer agent with low toxicity that is currently in development. The first economical, one-step synthesis of protoapigenone from apigenin is described on up to gram scale. 13 new 1'-O-alkylflavone analogs were also synthesized, either from apigenin or β-naphthoflavone. The in vitro cytotoxic activity of each compound was tested on six human cancer cell lines (HepG2, Hep3B, Ca9-22, A549, MCF-7 and MDA-MB-231). In the case of 1'-O-alkyl-protoapigenone derivatives, structure-activity relationships were found depending on the side-chain, and protoapigenone 1'-O-butyl ether was found to exert significantly stronger activity against three of the cell lines (Hep3B, MCF-7 and MDA-MB-231) than its non-substituted analog, protoapigenone itself. In contrast to this, all β-naphthoflavone derivatives bearing the same pharmacophore on their B-ring showed decreased cytotoxic activities when substituted with an O-alkyl side-chain at position 1', comparing to that of the non-substituted compound.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Journal of agricultural and food chemistry, 27 April 2011, Vol.59(8), pp.4288-93
    Description: We evaluated the possible anticancer performance of a natural compound, goniothalamin (GTN), against human lung cancer using as a non-small cell lung cancer (NSCLC) cell line, H1299, as the model system. Cellular proliferation was significantly inhibited by GTN. Using an improved alkaline comet-nuclear extract (comet-NE) assay, GTN was found to induce a significant increase in the tail DNA. Wound healing and zymography assays showed that GTN attenuated cell migration and caused a reduction in the activity level of two major migration-associated matrix metalloproteinases, MMP-2 and MMP-9. It can be concluded that the DNA-damaging effect of GTN against lung cancer cells leads to growth inhibition as well as a depression in migration ability. Therefore, GTN has potential as a chemotherapeutic agent against lung cancer.
    Keywords: Apoptosis -- Drug Effects ; Carcinoma, Non-Small-Cell Lung -- Pathology ; Cell Division -- Drug Effects ; Cell Movement -- Drug Effects ; DNA Damage -- Drug Effects ; Lung Neoplasms -- Pathology ; Pyrones -- Pharmacology
    ISSN: 00218561
    E-ISSN: 1520-5118
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  • 6
    Language: English
    In: Food Chemistry, 01 September 2013, Vol.140(1-2), pp.305-314
    Description: roots showed oestrogenic and anti-platelet activities. ► Twenty-six compounds were isolated and divided into 10 different skeletons. ► The biosynthetic pathway of the isolated dihydrobenzofuroisocoumarins was proposed. can be used to develop nutritional dietary supplements. The ethanolic extract of (Liliaceae) roots showed potential oestrogenic and anti-platelet activities. Twenty-six compounds were isolated and classified as 10 skeletons, including two unusual new dihydrobenzofuroisocoumarins, (+)-platyphyllarin A ( ) and B ( ), one new butanoate, ethyltributanoate ( ), and two new homoisoflavanones, (−)-liriopein A ( ) and B ( ), along with 21 known compounds, including six homoisoflavonoids, one chalcone, six amides, one lignan, one fatty acid derivative, one alkaloid, three benzenoids, and two steroids. The biosynthetic pathway of compounds and was proposed in the current investigation. The oestrogenic activity of the isolates was evaluated utilising the pER8:GUS reporter assay system in transgenic plant as well as the SEAP reporter assay system in MCF-7 breast cancer cell-line; the anti-platelet activity was evaluated using the anti-platelet aggregation assay. Several components exhibited significant oestrogenic and anti-platelet activities; demonstrating for the first time the potential use of as a nutritional supplement for cardiovascular and endocrine diseases.
    Keywords: Liriope Platyphylla ; Dihydrobenzofuroisocoumarin ; Homoisoflavonoid ; Oestrogenic Activity ; Anti-Platelet Effect ; Arabidopsis Per8:Gus Reporter Assay ; Chemistry ; Diet & Clinical Nutrition ; Economics
    ISSN: 0308-8146
    E-ISSN: 1873-7072
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(5), p.e64739
    Description: BACKGROUND:Most chemotherapeutic drugs for killing cancer cells are highly cytotoxic in normal cells, which limits their clinical applications. Therefore, a continuing challenge is identifying a drug that is hypersensitive to cancer cells but has minimal deleterious effects on healthy cells. The aims of this study were to evaluate the potential of 4β-hydroxywithanolide (4βHWE) for selectively killing cancer cells and to elucidate its related mechanisms. METHODOLOGY AND PRINCIPAL FINDINGS:Changes in survival, oxidative stress, DNA damage, and apoptosis signaling were compared between 4βHWE-treated oral cancer (Ca9-22) and normal fibroblast (HGF-1) cells. At 24 h and 48 h, the numbers of Ca9-22 cells were substantially decreased, but the numbers of HGF-1 cells were only slightly decreased. Additionally, the IC50 values for 4βHWE in the Ca9-22 cells were 3.6 and 1.9 µg/ml at 24 and 48 h, respectively. Time-dependent abnormal increases in ROS and dose-responsive mitochondrial depolarization can be exploited by using 4βHWE in chemotherapies for selectively killing cancer cells. Dose-dependent DNA damage measured by comet-nuclear extract assay and flow cytometry-based γ-H2AX/propidium iodide (PI) analysis showed relatively severer damage in the Ca9-22 cells. At both low and high concentrations, 4βHWE preferably perturbed the cell cycle in Ca9-22 cells by increasing the subG1 population and arrest of G1 or G2/M. Selective induction of apoptosis in Ca9-22 cells was further confirmed by Annexin V/PI assay, by preferential expression of phosphorylated ataxia-telangiectasia- and Rad3-related protein (p-ATR), and by cleavage of caspase 9, caspase 3, and poly ADP-ribose polymerase (PARP). CONCLUSIONS/SIGNIFICANCE:Together, the findings of this study, particularly the improved understanding of the selective killing mechanisms of 4βHWE, can be used to improve efficiency in killing oral cancer cells during chemoprevention and therapy.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: BMC Cancer, 01 February 2011, Vol.11(1), p.58
    Description: Abstract Background Histone modifications in tumorigenesis are increasingly recognized as important epigenetic factors leading to cancer. Increased phosphorylation levels of histone H3 as a result of aurora B and pMSK1 overexpression were observed in various tumors. We selected aurora B and MSK1 as representatives for testing various compounds and drugs, and found that squamocin, a bis-tetrahydrofuran annonaceous acetogenin, exerted a potent effect on histone H3 phosphorylation. Methods GBM8401, Huh-7, and SW620 cells were incubated with 15, 30, and 60 μM squamocin for 24 h. The expressions of mRNA and proteins were analyzed by qRT-PCR and Western blotting, respectively. The cell viability was determined by an MTT assay. Cell cycle distribution and apoptotic cells were analyzed by flow cytometry. Results Our results showed that squamocin inhibited the proliferation of GBM8401, Huh-7, and SW620 cells, arrested the cell cycle at the G1 phase, and activated both intrinsic and extrinsic pathways to apoptosis. In addition, we demonstrated that squamocin had the ability to modulate the phosphorylation levels of H3S10 (H3S10p) and H3S28 (H3S28p) in association with the downregulation of aurora B and pMSK1 expressions. Conclusions This study is the first to show that squamocin affects epigenetic alterations by modulating histone H3 phosphorylation at S10 and S28, providing a novel view of the antitumor mechanism of squamocin.
    Keywords: Medicine
    ISSN: 1471-2407
    E-ISSN: 1471-2407
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  • 9
    Language: English
    In: Life Sciences, 13 June 2013, Vol.92(22), pp.1081-1092
    Description: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. In this study, we explored the anti-cancer activity of WYC02-9, a synthetic protoapigenone, on human HCT116 CRC cells. The anti-cancer activity of WYC02-9 and its underlying mechanisms were analyzed using XTT cell proliferation assays, colony formation assays, FACS analysis, annexin V staining, immunoblotting analysis, reactive oxygen species (ROS) generation assays, soft agar assays, a nude mice xenograft study and immunohistochemistry assays. Data showed that WYC02-9 suppressed CRC cell growth by arresting cells at G2/M and inducing cell death via apoptotic pathways. Further analysis demonstrated that WYC02-9-induced apoptosis was mediated by the activation of a ROS-mediated MAPK14 pathway. An in vivo xenograft study revealed that WYC02-9 enhanced MAP2K3/6 and MAPK14 phosphorylation, induced apoptosis, and suppressed CRC tumor growth. WYC02-9 exerts its anti-tumor effect via ROS/MAPK14-induced apoptosis and has the potential to be developed as a chemotherapeutic agent for CRC.
    Keywords: Flavonoid ; Wyc02-9 ; Mapk14 ; Colorectal Cancer ; Sciences (General) ; Biology
    ISSN: 0024-3205
    E-ISSN: 1879-0631
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  • 10
    Language: English
    In: Toxicology in Vitro, April 2011, Vol.25(3), pp.699-707
    Description: Involvement of activities of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs) remains unsolved in norcantharidin-associated breast cancer cell apoptosis. This study investigated the anti-cancer effect of norcantharidin and its underlying mechanism in two human breast cancer cell lines, estrogen receptor (ER)− HS-578T and ER+ MCF-7 cells. Norcantharidin induced potent cytotoxicity and arrested cell growth through increasing phosphorylation of Chk1, Chk2 and total p21 and reducing cyclin B and cdc25c expression. It also induced apoptosis through extrinsic death receptor and intrinsic mitochondrial pathways by cytochrome release, caspase activation, oligonucleosome appearance, PARP cleavage, and aberration of Bcl-2 family protein expression and phosphorylation. Although norcantharidin did not affect STAT1, STAT3, and STAT5 protein expression, it suppressed STAT3 and STAT5 phosphorylation in HS-578T cells, whereas it up-regulated STAT1 phosphorylation and down-regulated STAT5 phosphorylation in MCF-7 cells. Moreover, norcantharidin activated MAPK family member proteins, extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), were all phosphorylated by treatment. Pretreatment with selective kinase inhibitors significantly attenuated the norcantharidin-induced cytotoxicity in breast cancer cells. These findings suggest the potential involvement of MAPK and STAT pathways in norcantharidin-induced apoptogenesis. Norcantharidin may be an effective anti-cancer drug against breast cancer.
    Keywords: Norcantharidin ; Chemosensitivity ; Breast Cancer ; Estrogen Receptor ; Signal Transducer and Activator of Transcription ; Mitogen-Activated Protein Kinase ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry ; Public Health
    ISSN: 0887-2333
    E-ISSN: 1879-3177
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