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Cell cycle modulatory and apoptotic effects of plant-derived anticancer drugs in clinical use or development
No full textDrugs derived from natural products, particularly from plants, are the leads of clinically used anticancer agents. Plant-derived anticancer agents in clinical use consist of the Vinca alkaloids, vinblastine and vincristine, camptothecin derivatives, paclitaxel, etoposide and teniposide, homoharringtonine and elliptinium. Extensive research has led to the identification of promising plant-derived anticancer agents in clinical development, namely flavopiridol, combretastatins and roscovitine. These compounds share common antitumor activities and signaling pathways targeting tumor cell cycle and cell death. 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A journey under the sea: The quest for marine anti-cancer alkaloids
No full textThe alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. 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Antiproliferative activities of Artemisia herba-alba ethanolic extract in human colon cancer cell line (HCT116)
No full textArtemisia herba-alba (AHE) is a plant commonly used in traditional medicine for the treatment of various ailments. Here, we investigated the antioxidant and antitumor activity of the aqueous and ethanol extracts of AHE in human
colon cancer HCT116 cells. The antioxidant activity was measured by DCFH assay, while antitumor effects were assessed by cell viability assays, cell cycle progression by flow cytometry, and DNA fragmentation analysis in addition to investigating the expression of key cell cycle and apoptotic proteins. While the aqueous extract had no antineoplastic effects, the ethanol extract significantly decreased HCT116 viability (IC50 of 51g/mL at 24 h) and inhibited the production of reactive oxygen species (ROS). Treatment of HCT116 cells with the ethanol extract also caused dramatic increase in the PreG1 population with concomitant decrease in cycling cells, provoked DNA fragmentation, significant increase in the expression levels of p53 and Bax proteins and activated pro-apoptotic caspase-3. The results obtained suggest that the ethanol extract of AHE could be used as an easily accessible source of natural antioxidants and as potential phytochemicals against colon cancer
Anti-colon cancer effects of Salograviolide A isolated from Centaurea ainetensis
No full textThe antitumor activity of extracts of Centaurea ainetensis (C. ainetensis), a plant endemic to Lebanon, was investigated in human colon carcinoma cells. At concentrations that were non-cytotoxic to normal human intestinal epithelial cells, the crude extract inhibited the proliferation of a host of colon-derived cancer cells. The crude extract effect was then investigated in HCT-116 (p513+-+) cells, most sensitive to treatment and was found to cause apoptosis, increase the Bax-Bcl-2 ratio, p53 and p21 protein levels and reduce cyclin B1 proteins. In vivo, the crude extract injected intraperitoneally before the subcutaneous injection of the carcinogen 1,2-dimethylhydrazine, drastically reduced the number of tumors and decreased the mean size of aberrant crypt foci. Further bioassay-guided fractionation of the crude extract resulted in the identification of the bioactive molecule Salograviolide A, a Sesquiterpene Lactone, to which the growth inhibition in colon cancer was linked. Salograviolide A, at non-cytotoxic concentrations to normal human intestinal cells, reduced the growth of colon cancer cell lines. Salograviolide A induced growth inhibition and resulted in an increased preG1 phase and presumably apoptosis induction which was further confirmed by TUNEL. These data support the testing of the C. ainetensis extract and its bioactive molecule, Salograviolide A, in colon cancer treatment.Akbar S, 1995, J ETHNOPHARMACOL, V49, P91; ARCHANA S, 2004, CANC LETT, V208, P127; Barrero AF, 2000, FITOTERAPIA, V71, P60, DOI 10.1016-S0367-326X(99)00122-7; Buruk K, 2006, FITOTERAPIA, V77, P388, DOI 10.1016-j.fitote.2006.03.002; Gali-Muhtasib H, 2004, INT J ONCOL, V25, P857; GIORDANO OS, 1992, J MED CHEM, V35, P2452, DOI 10.1021-jm00091a013; Kaïj-a-Kamb M, 1992, Pharm Acta Helv, V67, P178; Karamenderes C, 2007, PHYTOTHER RES, V21, P488, DOI 10.1002-ptr.2097; Koukoulitsa E, 2002, PLANTA MED, V68, P649, DOI 10.1055-s-2002-32893; Lee HJ, 2006, CARCINOGENESIS, V27, P2455, DOI 10.1093-carcin-bgl104; LEE KH, 1977, PHYTOCHEMISTRY, V16, P1177; LOBO J. M. VIGUERA, 1953, FARMACOGNOSIA [MADRID], V13, P223; MABBERLAY DJ, 1997, PLANT BOOK, pP440; MASKENS AP, 1976, CANCER RES, V36, P1585; Perse M, 2005, SCAND J GASTROENTERO, V40, P61, DOI 10.1080-00365520410009519; ROUWAYHA A, 1983, HERBAL TREATMENT, P1; ROUWAYHA A, 1981, ALATADAWI BIL AASHAB; Senderowicz AM, 2000, J NATL CANCER I, V92, P376, DOI 10.1093-jnci-92.5.376; Skaltsa H, 2000, PHYTOCHEMISTRY, V55, P903, DOI 10.1016-S0031-9422(00)00254-5; Skliar MI, 2005, FITOTERAPIA, V76, P737, DOI 10.1016-j.fitote.2005.08.006; Smith TK, 2003, CARCINOGENESIS, V24, P491, DOI 10.1093-carcin-24.3.491; Takizawa CG, 2000, CURR OPIN CELL BIOL, V12, P658, DOI 10.1016-S0955-0674(00)00149-6; Vajs V, 1999, PHYTOCHEMISTRY, V52, P383, DOI 10.1016-S0031-9422(99)00207-1; WEED HG, 1985, CARCINOGENESIS, V6, P1239, DOI 10.1093-carcin-6.8.123966
Thymoquinone induces apoptosis in human glioblastoma cell lines
No full textNigella sativa L. seeds have been traditionally employed for thousands of years as a spice and food preservative, as well as a protective and curative remedy for the treatment of inflammations, liver disorders, and arthritis in Middle Eastern. The main constituent of volatile oil is the thymoquinone (TQ). TQ is the bioactive component that possesses antioxidant, anti-inflammatory, anti-neoplastic, and hepato-protective properties. Previous studies demonstrated anti-cancer properties of TQ in several in vitro and in vivo tumor models. However, therapeutic efficacy of TQ has not been evaluated in glioblastoma. We investigated the effects of TQ against two human glioblastoma cell lines, U87 MG (p53 wild type) and T98G (p53 mutant). TQ decreases cell survival in a dose and time-dependent manner, and more significantly in U87 MG cells than in T98G cells. The cells exposed to 25, 50, and 100 μM TQ for 24 h showed morphological and biochemical features of apoptosis. Morphological changes, nuclear condensation, DNA fragmentation, caspases-9 and -3 activities, and reactive oxygen species (ROS) production were determined. Cell death was found to be apoptotic involving intrinsic pathways as evidenced by increase of caspase-9 activity. ROS were elevated following TQ treatment and antioxidant N-acetyl-cysteine prevented cell death in both cell lines. These findings suggest that TQ induces apoptosis via a mechanism involving ROS and oxidative stress pathway
Radiosensitization of EMT6 mammary carcinoma cells by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide
No full textBackground and purpose: Previously, we have reported that 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) is a radiosensitizer. Here, we investigate the mechanism of radiosensitization. Materials and methods: EMT6 cells were treated with DCQ for 4 h prior to ionizing radiation (IR). Flow cytometry, clonogenic assay, TUNEL, and Western blotting were performed to assess the effect of treatment on cells. Results: Propidium iodide staining of EMT6 cells treated with IR ± DCQ revealed high numbers of cells with decreased DNA, consistent with an apoptotic response. TUNEL assay revealed apoptosis was 4percent, 38percent, and 49percent 24 h after treatment with IR alone, DCQ alone, and DCQ + IR, respectively. Clonogenic assays revealed that the survival of irradiated EMT6 cells was significantly reduced by DCQ treatment. DCQ treatment abrogated the radiation-induced expression of p21 and p53. The increased apoptosis observed in DCQ + IR-treated cells was correlated to suppression of radiation-induced phosphorylation of Akt and the expression of Bcl-XL. DCQ also caused the phosphorylation of mitogen-activated protein kinases Erk and Jnk. Conclusions: The radiosensitization effect of DCQ occurs through enhancement of radiation-induced apoptosis, which correlates to the inhibition of p-Akt kinase and Bcl-XL and the activation of Erk and Jnk kinases, but appears independent of p53 induction or modulation of Bax-Bcl-2 gene expression. These data suggest DCQ should be tested as a radiosensitizer in vivo and has potential in the treatment of human solid tumors. © 2008.Adams JM, 1998, SCIENCE, V281, P1322, DOI 10.1126-science.281.5381.1322; Brugarolas J, 1999, P NATL ACAD SCI USA, V96, P1002, DOI 10.1073-pnas.96.3.1002; Cantley LC, 2002, SCIENCE, V296, P1655, DOI 10.1126-science.296.5573.1655; Chiosis G, 2001, BIOORG MED CHEM LETT, V11, P909, DOI 10.1016-S0960-894X(01)00099-3; Cory S, 2002, NAT REV CANCER, V2, P647, DOI 10.1038-nrc883; Dangi S, 2003, CELL SIGNAL, V15, P667, DOI 10.1016-S0898-6568(03)00002-0; Datta SR, 1999, GENE DEV, V13, P2905, DOI 10.1101-gad.13.22.2905; Davies SP, 2000, BIOCHEM J, V351, P95, DOI 10.1042-0264-6021:3510095; DIABASSAF M, 2000, MOL CARCINOG, V33, P198; Evan G, 1998, SCIENCE, V281, P1317, DOI 10.1126-science.281.5381.1317; Figueroa C, 2003, J BIOL CHEM, V278, P47922, DOI 10.1074-jbc.M307357200; Fukuchi K, 2000, BBA-MOL CELL RES, V1496, P207, DOI 10.1016-S0167-4889(00)00018-5; Gali-Muhtasib H, 2004, INT J ONCOL, V24, P1121; Gali-Muhtasib HU, 2005, CANCER CHEMOTH PHARM, V55, P369, DOI 10.1007-s00280-004-0907-x; Gali-Muhtasib HU, 2001, ONCOL REP, V8, P679; Gottlieb TM, 2002, ONCOGENE, V21, P1299, DOI 10.1038-sj-onc-1205181; Gottschalk AR, 2005, INT J RADIAT ONCOL, V63, P1221, DOI 10.1016-j.ijrobp.2005.08.014; Gupta AK, 2001, CANCER RES, V61, P4278; HADDADIN MJ, 1993, HETEROCYCLES, V35, P1503; Harakeh S, 2004, CHEM-BIOL INTERACT, V148, P101, DOI 10.1016-j.cbi.2004.05.002; Itani W., 2007, RAD ONCOL, V2; Kandel ES, 2002, MOL CELL BIOL, V22, P7831, DOI 10.1128-MCB.22.22.7831-7841.2002; Kim AH, 2002, NEURON, V35, P697, DOI 10.1016-S0896-6273(02)00821-8; Kirsch DG, 1998, J CLIN ONCOL, V16, P3158; Kluck RM, 1997, SCIENCE, V275, P1132, DOI 10.1126-science.275.5303.1132; Koniaras K, 2001, ONCOGENE, V20, P7453, DOI 10.1038-sj.onc.1204942; Levine AJ, 1997, CELL, V88, P323, DOI 10.1016-S0092-8674(00)81871-1; Li Qun, 2002, Current Topics in Medicinal Chemistry, V2, P939, DOI 10.2174-1568026023393318; Liang K, 2003, MOL CANCER THER, V2, P1113; Lozano G, 2000, NATURE, V404, P24, DOI 10.1038-35003670; Lu Yiling, 2003, Rev Clin Exp Hematol, V7, P205; Lu YJ, 1998, ONCOGENE, V16, P705, DOI 10.1038-sj.onc.1201585; Ma YY, 2000, ONCOGENE, V19, P2739, DOI 10.1038-sj.onc.1203597; McKenna WG, 2003, ONCOGENE, V22, P5866, DOI 10.1038-sj.onc.1206699; Nakamura JL, 2005, J NEURO-ONCOL, V71, P215, DOI 10.1007-s11060-004-1718-y; POWIS G, 1994, CANCER RES, V54, P2419; Price BD, 1996, CANCER RES, V56, P246; Riesterer O, 2004, INT J RADIAT ONCOL, V58, P361, DOI 10.1016-j.ijrobp.2003.09.050; Shayesteh L, 1999, NAT GENET, V21, P99, DOI 10.1038-5042; Shonai T, 2002, CELL DEATH DIFFER, V9, P963, DOI 10.1038-sj.cdd.4401050; Soderlund K, 2005, INT J ONCOL, V26, P25; Tang DM, 2002, J BIOL CHEM, V277, P12710, DOI 10.1074-jbc.M111598200; Tenzer A, 2001, CANCER RES, V61, P8203; Watanabe H, 2004, INT J RADIAT BIOL, V80, P451, DOI 10.1080-09553000410001702355; West KA, 2002, DRUG RESIST UPDATE, V5, P234, DOI 10.1016-S1368-7646(02)00120-6; Yang J, 2003, MUTAT RES-REV MUTAT, V543, P31, DOI 10.1016-S1383-5742(02)00069-8; YAO RJ, 1995, SCIENCE, V267, P2003, DOI 10.1126-science.7701324; Zhan M, 2004, HISTOL HISTOPATHOL, V19, P915; Zhang L, 2003, CANCER RES, V63, P422569
Thymoquinone-induced conformational changes of PAK1 interrupt prosurvival MEK-ERK signaling in colorectal cancer
No full textBackground: Thymoquinone (TQ) was shown to reduce tumor growth in several cancer models both in vitro and in vivo. So far only a few targets of TQ, including protein kinases have been identified. Considering that kinases are promising candidates for targeted anticancer therapy, we studied the complex kinase network regulated by TQ.Methods: Novel kinase targets influenced by TQ were revealed by in silico analysis of peptide array data obtained from TQ-treated HCT116wt cells. Western blotting and kinase activity assays were used to determine changes in kinase expression patterns in colorectal cancer cells (HCT116wt, DLD-1, HT29). To study the viability-apoptotic effects of combining the PAK1 inhibitor IPA-3 and TQ, crystal violet assay and AnnexinV-PI staining were employed. Interactions between PAK1 and ERK1-2 were investigated by co-immunoprecipitation and modeled by docking studies. Transfection with different PAK1 mutants unraveled the role of TQ-induced changes in PAK1 phosphorylation and TQ ´s effects on PAK1 scaffold function.Results: Of the 104 proteins identified, 50 were upregulated ≥2 fold by TQ and included molecules in the AKT-MEK-ERK1-2 pathway. Oncogenic PAK1 emerged as an interesting TQ target. Time-dependent changes in two PAK1 phosphorylation sites generated a specific kinase profile with early increase in pPAKThr212 followed by late increase in pPAKThr423. TQ induced an increase of pERK1-2 and triggered the early formation of an ERK1-2-PAK1 complex. Modeling confirmed that TQ binds in the vicinity of Thr212 accompanied by conformational changes in ERK2-PAK1 binding. Transfecting the cells with the non-phosphorylatable mutant T212A revealed an increase of pPAKThr423 and enhanced apoptosis. Likewise, an increase in apoptosis was observed in cells transfected with both the kinase-dead K299R mutant and PAK1 siRNA. Using structural modeling we suggest that TQ interferes also with the kinase domain consequently disturbing its interaction with pPAKThr423, finally inhibiting MEK-ERK1-2 signaling and disrupting its prosurvival function. pERK1-2 loss was also validated in vivo.Conclusions: Our study shows for the first time that the small molecule TQ directly binds to PAK1 changing its conformation and scaffold function. 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Gallotannin inhibits NFκB signaling and growth of human colon cancer xenografts
No full textGallotannin (GT), the polyphenolic hydrolyzable tannin, exhibits anti-inflammatory and anticancer activities through mechanisms that are not fully understood. Several effects modulated by GT have been shown to be linked to interference with inflammatory mediators. Considering the central role of nuclear factor kappaB (NFκB) in inflammation and cancer, we investigated the effect of GT on NFκB signaling in HT-29 and HCT-116 human colon cancer cells. DNA binding assays revealed significant suppression of tumor necrosis factor (TNFα)-induced NFκB activation which correlated with the inhibition of IκBα phosphorylation and degradation. Sequentially, p65 nuclear translocation and DNA binding were inhibited. GT also downregulated the expression of NFκB-regulated inflammatory cytokines (IL-8, TNFα, IL-1α) and caused cell cycle arrest and accumulation of cells in pre-G1 phase. In vivo, GT (25 mg-kg body weight) injected intraperitoneally (i.p.) prior to or after tumor inoculation significantly decreased the volume of human colon cancer xenografts in NOD-SCID mice. GT-treated xenografts showed significantly lower microvessel density (CD31) as well as lower mRNA expression levels of IL-6, TNFα and IL-1α and of the proliferation (Ki-67) and angiogenesis (VEGFA) proteins, which may explain GTs in vivo anti-tumorigenic effects. Overall, our results indicate that the anti-inflammatory and antitumor activities of GT may be mediated in part through the suppression of NFκB activation. © 2011 Landes Bioscience.Al-Ayyoubi S, 2007, MOL CARCINOGEN, V46, P176, DOI 10.1002-mc.20252; Chen KS, 2009, LEUKEMIA RES, V33, P297, DOI 10.1016-j.leukres.2008.08.006; Dhanalakshmi S, 2002, ONCOGENE, V21, P1759, DOI 10.1038-sj-onc-1205240; Erdelyi K, 2005, MOL PHARMACOL, V68, P895, DOI 10.1124-mol.105.012518; Feldman KS, 2001, BIOORG MED CHEM LETT, V11, P1813, DOI 10.1016-S0960-894X(01)00332-8; Gali-Muhtasib H, 2004, INT J ONCOL, V25, P857; Gali-Muhtasib HU, 2001, NUTR CANCER, V39, P108, DOI 10.1207-S15327914nc391_15; Ghosh S, 2008, NAT REV IMMUNOL, V8, P837, DOI 10.1038-nri2423; Hu HB, 2008, MOL CANCER THER, V7, P2681, DOI 10.1158-1535-7163.MCT-08-0456; Hu HB, 2009, CARCINOGENESIS, V30, P818, DOI 10.1093-carcin-bgp059; Iordachei S, 2010, J GASTROINTEST LIVER, V19, P135; KAUR M, 2011, CHEM-BIOL INTERACT, V15, P52; Kim MS, 2009, BIOL PHARM BULL, V32, P1053, DOI 10.1248-bpb.32.1053; Koleckar V, 2008, MINI-REV MED CHEM, V8, P436, DOI 10.2174-138955708784223486; Kuo PT, 2009, J AGR FOOD CHEM, V57, P3331, DOI 10.1021-jf803725h; Lee SJ, 2003, ARCH PHARM RES, V26, P832, DOI 10.1007-BF02980029; Li SH, 2007, MODERN PATHOL, V20, P497, DOI 10.1038-modpathol.3800762; Moreno R, 2010, NUCLEIC ACIDS RES, V38, P6029, DOI 10.1093-nar-gkq439; Nakamura Y, 2003, J AGR FOOD CHEM, V51, P331, DOI 10.1021-jf020847+; PERCHELLET JP, 1992, BASIC LIFE SCI, V59, P783; Pikarsky E, 2004, NATURE, V431, P461, DOI 10.1038-nature02924; Prasad S, 2010, MOL CELL BIOCHEM, V336, P25, DOI 10.1007-s11010-009-0267-2; PTASZYNSKA MM, 2008, MOL CANCER RES, V3, P352; Rapizzi E, 2004, MOL PHARMACOL, V66, P890, DOI 10.1124-mol.104.000968; Serrano J, 2009, MOL NUTR FOOD RES, V53, P310; Tergaonkar V, 2006, INT J BIOCHEM CELL B, V38, P1647, DOI 10.1016-j.biocel.2006.03.023; YERUSHALMI R, 2010, LANCET ONCOL, V1, P174; Yoon JH, 2005, YONSEI MED J, V46, P58510111
Inhibition of proliferation and induction of apoptosis by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide in adult T-cell leukemia cells
No full textHuman T-cell lymphotrophic virus type-1 (HTLV-1) is a retrovirus which causes adult T-cell leukemia (ATL), an aggressive malignancy of activated T-cells. So far, there is no proven therapy for this disease. The compound 2-benzoyl-3-phenyl-6,7-dichloro quinoxaline 1,4-dioxide (DCQ) has been shown to exhibit a wide range of antibacterial activities and to induce antiproliferation and apoptosis of human colon cancer cell lines. In the present study, we investigated the in vitro effects of DCQ in HTLV-1 positive (C91-PL and HuT-102) and negative (CEM and Jurkat) malignant T-cells. The results indicate that DCQ induced growth inhibition in all four cell lines examined in a dose-dependent manner. The inhibitory effect was mainly due to the induction of apoptosis which was verified by flow cytometry analyses and ELISA-based apoptosis assays. The role of transforming growth factor (TGF) in mediating the antiproliferative and apoptotic effects of DCQ in ATL cells was investigated. Interestingly, in three of the four cell lines used, DCQ increased the TGF-β1 transcript levels and decreased TGF-α mRNA, but did not induce changes in TGF-β2 expression. DCQ treatment also induced an upregulation of p53 and p21 protein levels, key mediators of cell cycle arrest and apoptosis. The anti-apoptotic Bcl-2α protein level was found to be reduced. These findings indicate that DCQ inhibits the growth of ATL cell lines, at least in part, by inducing apoptosis mediated by the modulation of TGF expression, the upregulation in p53 and p21 proteins and downregulation in Bcl-2α expression. The present findings suggest that DCQ merits further investigation as a potential therapeutic agent for this incurable disease. © 2004 Elsevier Ireland Ltd. All rights reserved.ALEXANDROW MG, 1995, CANCER RES, V55, P1452; Ashcroft M, 1999, MOL CELL BIOL, V19, P1751; Bazarbachi A, 1999, BLOOD, V93, P278; Bazarbachi A, 1996, J ACQ IMMUN DEF SYND, V13, pS186, DOI 10.1097-00042560-199600001-00028; BRADY J, 1987, J VIROL, V61, P2175; Bunz F, 1999, J CLIN INVEST, V104, P263, DOI 10.1172-JCI6863; Carta A, 2002, EUR J MED CHEM, V37, P355, DOI 10.1016-S0223-5234(02)01346-6; Colgin MA, 1998, J VIROL, V72, P9396; CROSS SL, 1987, CELL, V49, P47, DOI 10.1016-0092-8674(87)90754-9; DEMARTIN R, 1987, EMBO J, V6, P3673; Diab-Assef M, 2002, MOL CARCINOGEN, V33, P198, DOI 10.1002-mc.10036; DIRLAM JP, 1979, J MED CHEM, V22, P1118, DOI 10.1021-jm00195a022; Dunker N, 2002, GASTROENTEROLOGY, V122, P1364, DOI 10.1053-gast.2002.32991; El-Sabban ME, 2000, BLOOD, V96, P2849; FOLEY GE, 1965, CANCER, V18, P522, DOI 10.1002-1097-0142(196504)18:4522::AID-CNCR28201804183.0.CO;2-J; FUJII M, 1988, P NATL ACAD SCI USA, V85, P8526, DOI 10.1073-pnas.85.22.8526; Gali-Muhtasib H, 2004, INT J ONCOL, V24, P1121; Gali-Muhtasib HU, 2001, ONCOL REP, V8, P679; Gessain A., 1996, HUMAN T CELL LYMPHOT, P33; GREEN PL, 1994, RETROVIRIDAE, V3, P227; HADDADIN MJ, 1993, HETEROCYCLES, V35, P1503; HINUMA Y, 1982, INT J CANCER, V29, P631, DOI 10.1002-ijc.2910290606; Hollsberg P, 1999, MICROBIOL MOL BIOL R, V63, P308; HOSKIN BD, 1972, VET REC, V90, P396; INOUE J, 1986, EMBO J, V5, P2883; Jin DY, 1999, J BIOL CHEM, V274, P17402, DOI 10.1074-jbc.274.25.17402; Kanai M, 2001, GASTROENTEROLOGY, V121, P56, DOI 10.1053-gast.2001.25544; Kaplan JE, 1996, J ACQ IMMUN DEF SYND, V12, P193; KEHRL JH, 1986, J EXP MED, V163, P1037, DOI 10.1084-jem.163.5.1037; Low KG, 1997, J VIROL, V71, P1956; MARUYAMA M, 1987, CELL, V48, P343, DOI 10.1016-0092-8674(87)90437-5; MIYATAKE S, 1988, MOL CELL BIOL, V8, P5581; MIYOSHI I, 1980, GANN, V71, P155; Mortenson M.M., 2003, J SURG RES, V114, P302, DOI 10.1016-j.jss.2003.08.103; NAGATA K, 1989, J VIROL, V63, P3220; OHTANI K, 1989, NUCLEIC ACIDS RES, V17, P1589, DOI 10.1093-nar-17.4.1589; SCHONFELDER D, 1988, PHARMAZIE, V43, P837; SEIKI M, 1986, EMBO J, V5, P561; SHIMOYAMA M, 1992, GANN MONOGRAPH CANCE, V39, P43; SIEKEVITZ M, 1987, P NATL ACAD SCI USA, V84, P5389, DOI 10.1073-pnas.84.15.5389; SUTTER W, 1978, ANTIMICROB AGENTS CH, V13, P770; Takabatake T, 1996, YAKUGAKU ZASSHI, V116, P491; Tsukasaki K, 1997, BLOOD, V89, P948; Van Orden K, 1999, J BIOL CHEM, V274, P26321, DOI 10.1074-jbc.274.37.26321; WAHL SM, 1992, J CLIN IMMUNOL, V12, P61, DOI 10.1007-BF00918135; Wang DG, 2002, ONCOGENE, V21, P2785, DOI 10.1038-sj-onc-1205375; WANO Y, 1988, P NATL ACAD SCI USA, V85, P9733, DOI 10.1073-pnas.85.24.973314151
Cell death by the quinoxaline dioxide DCQ in human colon cancer cells is enhanced under hypoxia and is independent of p53 and p21
No full textAbstract Introduction We have shown that the radio sensitizer DCQ enhances sensitivity of HCT116 human colon cancer cells to hypoxia. However, it is not known whether the p53 or p21 genes influence cellular response to DCQ. In this study, we used HCT116 that are either wildtype for p53 and p21, null for p53 or null for p21 to understand the role of these genes in DCQ toxicity. Methods HCT116 cells were exposed to DCQ and incubated under normoxia or hypoxia and the viability, colony forming ability, DNA damage and apoptotic responses of these cells was determined, in addition to the modulation of HIF-1α and of p53, p21, caspase-2, and of the ataxia telangiectasia mutated (ATM) target PIDD-C. Results DCQ decreased colony forming ability and viability of all HCT116 cells to a greater extent under hypoxia than normoxia and the p21-/-cell line was most sensitive. Cells had different HIF-1α responses to hypoxia and/or drug treatment. In p53+/+, DCQ significantly inhibited the hypoxia-induced increases in HIF-1α protein, in contrast to the absence of a significant HIF-1α increase or modulation by DCQ in p21-/- cells. In p53-/- cells, 10 μM DCQ significantly reduced HIF-1α expression, especially under hypoxia, despite the constitutive expression of this protein in control cells. Higher DCQ doses induced PreG1-phase increase and apoptosis, however, lower doses caused mitotic catastrophe. In p53+/+ cells, apoptosis correlated with the increased expression of the pro-apoptotic caspase-2 and inhibition of the pro-survival protein PIDD-C. Exposure of p53+/+ cells to DCQ induced single strand breaks and triggered the activation of the nuclear kinase ATM by phosphorylation at Ser-1981 in all cell cycle phases. On the other hand, no drug toxicity to normal FHs74 Int human intestinal cell line was observed. Conclusions Collectively, our findings indicate that DCQ reduces the colony survival of HCT116 and induces apoptosis even in cells that are null for p53 or p21, which makes it a molecule of clinical significance, since many resistant colon tumors harbor mutations in p53.</p
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