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標題: 探討新穎喹唑啉酮衍生物對於抗血癌與口腔癌離體外細胞凋亡與抗轉移機轉探討和活體中抗腫瘤活性的研究
Investigations for targeting signaling pathways in the apoptosis induction and anti-metastasis of the novel quinazolinone derivatives in leukemia and oral cancer cells in vitro and anti-tumor activity in vivo
作者: 呂啟誠
Lu, Chi-Cheng
關鍵字: Quinazolinone derivatives;喹唑啉酮衍生物;leukemia;oral carcinoma;apoptosis;metastasis;leukemic mice;tumor xenografts;血癌;口腔癌;細胞凋亡;轉移;血癌小鼠;異種移植腫瘤
出版社: 生命科學系所
引用: Astashkin, EI, Til''kunova NA, Zalepugin DY, Grachev SV. Diallyl sulfide depletes the inositol trisphosphate-sensitive intracellular Ca2+ stores and activates SOC-channels in HL-60 human cells. Dokl Biol Sci. 2004;399:500-502. Babykutty, S, S PP, J NR, Kumar MA, Nair MS, Srinivas P, Gopala S. Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-kappaB in colon cancer cells. Mol Carcinog. 2012;51:475-490. Berridge, MJ, Bootman MD, Lipp P. Calcium--a life and death signal. Nature. 1998;395:645-648. Bhalla, KN. Microtubule-targeted anticancer agents and apoptosis. Oncogene. 2003;22:9075-9086. Boya, P, Cohen I, Zamzami N, Vieira HL, Kroemer G. Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell Death Differ. 2002;9:465-467. Boyce, M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005;307:935-939. Boyce, M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 2006;13:363-373. Breckenridge, DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene. 2003;22:8608-8618. Ceruti, S, Beltrami E, Matarrese P, Mazzola A, Cattabeni F, Malorni W, Abbracchio MP. A key role for caspase-2 and caspase-3 in the apoptosis induced by 2-chloro-2''-deoxy-adenosine (cladribine) and 2-chloro-adenosine in human astrocytoma cells. Mol Pharmacol. 2003;63:1437-1447. Chang, YH, Yang JS, Kuo SC, Chung JG. Induction of mitotic arrest and apoptosis by a novel synthetic quinolone analogue, CWC-8, via intrinsic and extrinsic apoptotic pathways in human osteogenic sarcoma U-2 OS cells. Anticancer Res. 2009a;29:3139-3148. Chang, YH, Yang JS, Yang JL, Wu CL, Chang SJ, Lu KW, Lin JJ, Hsia TC, Lin YT, Ho CC, Wood WG, Chung JG. Ganoderma lucidum extracts inhibited leukemia WEHI-3 cells in BALB/c mice and promoted an immune response in vivo. Biosci Biotechnol Biochem. 2009b;73:2589-2594. Chen, JC, Chung JG, Lin KM. Effects of luteolin on arylamine N-acetyltransferase activity in human liver tumour cells. Cytobios. 2000;102:95-106. Chen, YC, Lu PH, Pan SL, Teng CM, Kuo SC, Lin TP, Ho YF, Huang YC, Guh JH. Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. Biochem Pharmacol. 2007;74:10-19. Chen, YJ, Lin SC, Kao T, Chang CS, Hong PS, Shieh TM, Chang KW. Genome-wide profiling of oral squamous cell carcinoma. J Pathol. 2004;204:326-332. Chen, YY, Chiang SY, Lin JG, Ma YS, Liao CL, Weng SW, Lai TY, Chung JG. Emodin, aloe-emodin and rhein inhibit migration and invasion in human tongue cancer SCC-4 cells through the inhibition of gene expression of matrix metalloproteinase-9. Int J Oncol. 2010;36:1113-1120. Cheng, KL, Bradley T, Budman DR. Novel microtubule-targeting agents - the epothilones. Biologics. 2008;2:789-811. Chiang, JH, Yang JS, Ma CY, Yang MD, Huang HY, Hsia TC, Kuo HM, Wu PP, Lee TH, Chung JG. Danthron, an anthraquinone derivative, induces DNA damage and caspase cascades-mediated apoptosis in SNU-1 human gastric cancer cells through mitochondrial permeability transition pores and Bax-triggered pathways. Chem Res Toxicol. 2011;24:20-29. Chien, MH, Ying TH, Hsieh YS, Chang YC, Yeh CM, Ko JL, Lee WS, Chang JH, Yang SF. Dioscorea nipponica Makino inhibits migration and invasion of human oral cancer HSC-3 cells by transcriptional inhibition of matrix metalloproteinase-2 through modulation of CREB and AP-1 activity. Food Chem Toxicol. 2012;50:558-566. Choi, AY, Choi JH, Yoon H, Hwang KY, Noh MH, Choe W, Yoon KS, Ha J, Yeo EJ, Kang I. Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. Eur J Pharmacol. 2011;668:115-126. Choi, Y, Kim SY, Kim SH, Yang J, Park K, Byun Y. Inhibition of tumor growth by biodegradable microspheres containing all-trans-retinoic acid in a human head-and-neck cancer xenograft. Int J Cancer. 2003;107:145-148. Chou, LC, Yang JS, Huang LJ, Wu HC, Lu CC, Chiang JH, Chen KT, Kuo SC, Chung JG. The synthesized 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1) promoted G2/M arrest through inhibition of CDK1 and induced apoptosis through the mitochondrial-dependent pathway in CT-26 murine colorectal adenocarcinoma cells. J Gastroenterol. 2009;44:1055-1063. Christiansen, JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006;66:8319-8326. Chung, JG, Yang JS, Huang LJ, Lee FY, Teng CM, Tsai SC, Lin KL, Wang SF, Kuo SC. Proteomic approach to studying the cytotoxicity of YC-1 on U937 leukemia cells and antileukemia activity in orthotopic model of leukemia mice. Proteomics. 2007;7:3305-3317. Crowley-Weber, CL, Dvorakova K, Crowley C, Bernstein H, Bernstein C, Garewal H, Payne CM. Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chem Biol Interact. 2003;145:53-66. Dejeans, N, Tajeddine N, Beck R, Verrax J, Taper H, Gailly P, Calderon PB. Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells. Biochem Pharmacol. 2010;79:1221-1230. Deng, YT, Lin JK. EGCG inhibits the invasion of highly invasive CL1-5 lung cancer cells through suppressing MMP-2 expression via JNK signaling and induces G2/M arrest. J Agric Food Chem. 2011;59:13318-13327. Dong, Y, Tan J, Cui MZ, Zhao G, Mao G, Singh N, Xu X. Calpain inhibitor MDL28170 modulates Abeta formation by inhibiting the formation of intermediate Abeta46 and protecting Abeta from degradation. FASEB J. 2006;20:331-333. Donze, O, Jagus R, Koromilas AE, Hershey JW, Sonenberg N. Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J. 1995;14:3828-3834. Dumontet, C, Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010;9:790-803. Ermak, G, Davies KJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol. 2002;38:713-721. Fan, MJ, Lin YC, Shih HD, Yang JS, Liu KC, Yang ST, Lin CY, Wu RS, Yu CS, Ko YC, Chung JG. Crude extracts of Agaricus brasiliensis induce apoptosis in human oral cancer CAL 27 cells through a mitochondria-dependent pathway. In Vivo. 2011;25:355-366. Ferri, KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001;3:E255-263. Fisher, RP, Morgan DO. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell. 1994;78:713-724. Funk, GF, Karnell LH, Robinson RA, Zhen WK, Trask DK, Hoffman HT. Presentation, treatment, and outcome of oral cavity cancer: a National Cancer Data Base report. Head Neck. 2002;24:165-180. Funk, RK, Maxwell TJ, Izumi M, Edwin D, Kreisel F, Ley TJ, Cheverud JM, Graubert TA. Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice. Blood. 2008;112:1434-1442. Furre, IE, Shahzidi S, Luksiene Z, Moller MT, Borgen E, Morgan J, Tkacz-Stachowska K, Nesland JM, Peng Q. Targeting PBR by hexaminolevulinate-mediated photodynamic therapy induces apoptosis through translocation of apoptosis-inducing factor in human leukemia cells. Cancer Res. 2005;65:11051-11060. Green, DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309-1312. He, Q, Na X. The effects and mechanisms of a novel 2-aminosteroid on murine WEHI-3B leukemia cells in vitro and in vivo. Leuk Res. 2001;25:455-461. Heid, CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR. Genome Res. 1996;6:986-994. Hendriks, JJ, Slaets H, Carmans S, de Vries HE, Dijkstra CD, Stinissen P, Hellings N. Leukemia inhibitory factor modulates production of inflammatory mediators and myelin phagocytosis by macrophages. J Neuroimmunol. 2008;204:52-57. Hidalgo, M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst. 2001;93:178-193. Ho, YT, Yang JS, Lu CC, Chiang JH, Li TC, Lin JJ, Lai KC, Liao CL, Lin JG, Chung JG. Berberine inhibits human tongue squamous carcinoma cancer tumor growth in a murine xenograft model. Phytomedicine. 2009;16:887-890. Hooper, DC. Mode of action of fluoroquinolones. Drugs. 1999;58 Suppl 2:6-10. Hour, MJ, Huang LJ, Kuo SC, Xia Y, Bastow K, Nakanishi Y, Hamel E, Lee KH. 6-Alkylamino- and 2,3-dihydro-3''-methoxy-2-phenyl-4-quinazolinones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J Med Chem. 2000;43:4479-4487. Hour, MJ, Yang JS, Lien JC, Kuo SC, Huang LJ. Synthesis and cytotoxicity of 6-pyrrolidinyl-2-(2-substituted phenyl)-4-quinazolinones. J Chin Chem Soc. 2007;54:785-790. Hsu, SC, Ou CC, Li JW, Chuang TC, Kuo HP, Liu JY, Chen CS, Lin SC, Su CH, Kao MC. Ganoderma tsugae extracts inhibit colorectal cancer cell growth via G(2)/M cell cycle arrest. J Ethnopharmacol. 2008;120:394-401. Huang, LJ, Hsieh MC, Teng CM, Lee KH, Kuo SC. Synthesis and antiplatelet activity of phenyl quinolones. Bioorg Med Chem. 1998;6:1657-1662. Huang, WW, Chiu YJ, Fan MJ, Lu HF, Yeh HF, Li KH, Chen PY, Chung JG, Yang JS. Kaempferol induced apoptosis via endoplasmic reticulum stress and mitochondria-dependent pathway in human osteosarcoma U-2 OS cells. Mol Nutr Food Res. 2010;54:1585-1595. Huang, YT, Huang DM, Guh JH, Chen IL, Tzeng CC, Teng CM. CIL-102 interacts with microtubule polymerization and causes mitotic arrest following apoptosis in the human prostate cancer PC-3 cell line. J Biol Chem. 2005;280:2771-2779. Itzykson, R, Ayari S, Vassilief D, Berger E, Slama B, Vey N, Suarez F, Beyne-Rauzy O, Guerci A, Cheze S, Thomas X, Stamatoullas A, Gardembas M, Bauduer F, Kolb A, Chaury MC, Legros L, Damaj G, Chermat F, Dreyfus F, Fenaux P, Ades L. Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases. Leukemia. 2009;23:673-678. Ji, BC, Hsu WH, Yang JS, Hsia TC, Lu CC, Chiang JH, Yang JL, Lin CH, Lin JJ, Suen LJ, Gibson Wood W, Chung JG. Gallic acid induces apoptosis via caspase-3 and mitochondrion-dependent pathways in vitro and suppresses lung xenograft tumor growth in vivo. J Agric Food Chem. 2009;57:7596-7604. Jiang, L, Ji N, Zhou Y, Li J, Liu X, Wang Z, Chen Q, Zeng X. CAL 27 is an oral adenosquamous carcinoma cell line. Oral Oncol. 2009;45:e204-207. Jiang, L, Liu X, Kolokythas A, Yu J, Wang A, Heidbreder CE, Shi F, Zhou X. Downregulation of the Rho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion in tongue squamous cell carcinoma. Int J Cancer. 2010;127:505-512. Kadowaki, H, Nishitoh H, Ichijo H. Survival and apoptosis signals in ER stress: the role of protein kinases. J Chem Neuroanat. 2004;28:93-100. Kan, SF, Huang WJ, Lin LC, Wang PS. Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP. Int J Cancer. 2004;110:641-651. Kavallaris, M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer. 2010;10:194-204. Kelloff, GJ, Crowell JA, Steele VE, Lubet RA, Malone WA, Boone CW, Kopelovich L, Hawk ET, Lieberman R, Lawrence JA, Ali I, Viner JL, Sigman CC. Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. J Nutr. 2000;130:467S-471S. Kim, I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7:1013-1030. Kim, R, Emi M, Tanabe K, Murakami S. Role of the unfolded protein response in cell death. Apoptosis. 2006;11:5-13. Kim, SA, Kwon SM, Kim JA, Kang KW, Yoon JH, Ahn SG. 5''-Nitro-indirubinoxime, an indirubin derivative, suppresses metastatic ability of human head and neck cancer cells through the inhibition of Integrin beta1/FAK/Akt signaling. Cancer Lett. 2011;306:197-204. Kroemer, G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87:99-163. Kumar, S, Bryant CS, Chamala S, Qazi A, Seward S, Pal J, Steffes CP, Weaver DW, Morris R, Malone JM, Shammas MA, Prasad M, Batchu RB. Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells. Mol Cancer. 2009;8:26. Kuo, YF, Su YZ, Tseng YH, Wang SY, Wang HM, Chueh PJ. Flavokawain B, a novel chalcone from Alpinia pricei Hayata with potent apoptotic activity: Involvement of ROS and GADD153 upstream of mitochondria-dependent apoptosis in HCT116 cells. Free Radic Biol Med. 2010;49:214-226. Lai, E, Teodoro T, Volchuk A. Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda). 2007;22:193-201. Lai, KC, Huang AC, Hsu SC, Kuo CL, Yang JS, Wu SH, Chung JG. Benzyl isothiocyanate (BITC) inhibits migration and invasion of human colon cancer HT29 cells by inhibiting matrix metalloproteinase-2/-9 and urokinase plasminogen (uPA) through PKC and MAPK signaling pathway. J Agric Food Chem. 2010;58:2935-2942. Landrigan, PJ. Childhood leukemias. N Engl J Med. 1995;333:1286. Lavrik, IN, Golks A, Krammer PH. Caspases: pharmacological manipulation of cell death. J Clin Invest. 2005;115:2665-2672. Lee, EJ, Kim DI, Kim WJ, Moon SK. Naringin inhibits matrix metalloproteinase-9 expression and AKT phosphorylation in tumor necrosis factor-alpha-induced vascular smooth muscle cells. Mol Nutr Food Res. 2009;53:1582-1591. Lee, H, Park MT, Choi BH, Oh ET, Song MJ, Lee J, Kim C, Lim BU, Park HJ. Endoplasmic reticulum stress-induced JNK activation is a critical event leading to mitochondria-mediated cell death caused by beta-lapachone treatment. PLoS One. 2011a;6:e21533. Lee, KW, Bode AM, Dong Z. Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer. 2011b;11:211-218. Lee, SJ, Kim KH, Park JS, Jung JW, Kim YH, Kim SK, Kim WS, Goh HG, Kim SH, Yoo JS, Kim DW, Kim KP. Comparative analysis of cell surface proteins in chronic and acute leukemia cell lines. Biochem Biophys Res Commun. 2007;357:620-626. Lee, ST, Wong PF, Cheah SC, Mustafa MR. Alpha-tomatine induces apoptosis and inhibits nuclear factor-kappa B activation on human prostatic adenocarcinoma PC-3 cells. PLoS One. 2011c;6:e18915. Li, L, Han W, Gu Y, Qiu S, Lu Q, Jin J, Luo J, Hu X. Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore. Cancer Res. 2007;67:4894-4903. Liabakk, NB, Talbot I, Smith RA, Wilkinson K, Balkwill F. Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res. 1996;56:190-196. Liang, X, Yang X, Tang Y, Zhou H, Liu X, Xiao L, Gao J, Mao Z. RNAi-mediated downregulation of urokinase plasminogen activator receptor inhibits proliferation, adhesion, migration and invasion in oral cancer cells. Oral Oncol. 2008;44:1172-1180. Liao, PC, Tan SK, Lieu CH, Jung HK. Involvement of endoplasmic reticulum in paclitaxel-induced apoptosis. J Cell Biochem. 2008;104:1509-1523. Lin, HJ, Su CC, Lu HF, Yang JS, Hsu SC, Ip SW, Wu JJ, Li YC, Ho CC, Wu CC, Chung JG. Curcumin blocks migration and invasion of mouse-rat hybrid retina ganglion cells (N18) through the inhibition of MMP-2, -9, FAK, Rho A and Rock-1 gene expression. Oncol Rep. 2010a;23:665-670. Lin, HY, Masso-Welch P, Di YP, Cai JW, Shen JW, Subjeck JR. The 170-kDa glucose-regulated stress protein is an endoplasmic reticulum protein that binds immunoglobulin. Mol Biol Cell. 1993;4:1109-1119. Lin, JP, Yang JS, Lin JJ, Lai KC, Lu HF, Ma CY, Sai-Chuen Wu R, Wu KC, Chueh FS, Gibson Wood W, Chung JG. Rutin inhibits human leukemia tumor growth in a murine xenograft model in vivo. Environ Toxicol. 2011. Lin, SS, Hung CF, Ho CC, Liu YH, Ho HC, Chung JG. Effects of ellagic acid by oral administration on N-acetylation and metabolism of 2-aminofluorene in rat brain tissues. Neurochem Res. 2000;25:1503-1508. Lin, SY, Sheen LY, Chiang BH, Yang JS, Pan JH, Chang YH, Hsu YM, Chiang JH, Lu CC, Wu CL, Chung JG. Dietary effect of Antrodia Camphorate extracts on immune responses in WEHI-3 leukemia BALB/c mice. Nutr Cancer. 2010b;62:593-600. Liu, JF, Fong YC, Chang KW, Kuo SC, Chang CS, Tang CH. FPTB, a novel CA-4 derivative, induces cell apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress pathways. J Cell Biochem. 2011;112:453-462. Liu, SY, Lu CL, Chiou CT, Yen CY, Liaw GA, Chen YC, Liu YC, Chiang WF. Surgical outcomes and prognostic factors of oral cancer associated with betel quid chewing and tobacco smoking in Taiwan. Oral Oncol. 2010a;46:276-282. Liu, T, Raetz E, Moos PJ, Perkins SL, Bruggers CS, Smith F, Carroll WL. Diversity of the apoptotic response to chemotherapy in childhood leukemia. Leukemia. 2002;16:223-232. Liu, W, Lee HW, Liu Y, Wang R, Rodgers GP. Olfactomedin 4 is a novel target gene of retinoic acids and 5-aza-2''-deoxycytidine involved in human myeloid leukemia cell growth, differentiation, and apoptosis. Blood. 2010b;116:4938-4947. Lo, WL, Kao SY, Chi LY, Wong YK, Chang RC. Outcomes of oral squamous cell carcinoma in Taiwan after surgical therapy: factors affecting survival. J Oral Maxillofac Surg. 2003;61:751-758. Lu, CC, Yang JS, Chiang JH, Hour MJ, Lin KL, Lin JJ, Huang WW, Tsuzuki M, Lee TH, Chung JG. Novel quinazolinone MJ-29 triggers endoplasmic reticulum stress and intrinsic apoptosis in murine leukemia WEHI-3 cells and inhibits leukemic mice. PLoS One. 2012a. Lu, CC, Yang JS, Chiang JH, Hour MJ, Lin KL, Lin JJ, Huang WW, Tsuzuki M, Lee TH, Chung JG. Novel Quinazolinone MJ-29 Triggers Endoplasmic Reticulum Stress and Intrinsic Apoptosis in Murine Leukemia WEHI-3 Cells and Inhibits Leukemic Mice. PLoS One. 2012b;7:e36831. Lu, CC, Yang JS, Huang AC, Hsia TC, Chou ST, Kuo CL, Lu HF, Lee TH, Wood WG, Chung JG. Chrysophanol induces necrosis through the production of ROS and alteration of ATP levels in J5 human liver cancer cells. Mol Nutr Food Res. 2010;54:967-976. Lu, Z, Lu N, Li C, Li F, Zhao K, Lin B, Guo Q. Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway. Toxicol Lett. 2012c;209:211-220. Matsuzaki, S, Hiratsuka T, Kuwahara R, Katayama T, Tohyama M. Caspase-4 is partially cleaved by calpain via the impairment of Ca2+ homeostasis under the ER stress. Neurochem Int. 2010;56:352-356. McCullough, KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21:1249-1259. Moretta, L. NK cell-mediated immune response against cancer. Surg Oncol. 2007;16 Suppl 1:S3-5. Morris, PG, Fornier MN. Microtubule active agents: beyond the taxane frontier. Clin Cancer Res. 2008;14:7167-7172. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55-63. Moungjaroen, J, Nimmannit U, Callery PS, Wang L, Azad N, Lipipun V, Chanvorachote P, Rojanasakul Y. Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation. J Pharmacol Exp Ther. 2006;319:1062-1069. Mozaffarieh, M, Konieczka K, Hauenstein D, Schoetzau A, Flammer J. Half a pack of cigarettes a day more than doubles DNA breaks in circulating leukocytes. Tob Induc Dis. 2010;8:14. Muir, C, Weiland L. Upper aerodigestive tract cancers. Cancer. 1995;75:147-153. Muraki, C, Ohga N, Hida Y, Nishihara H, Kato Y, Tsuchiya K, Matsuda K, Totsuka Y, Shindoh M, Hida K. Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells. Int J Cancer. 2012;130:59-70. Murray, AW. Recycling the cell cycle: cyclins revisited. Cell. 2004;116:221-234. Nam, S, Smith DM, Dou QP. Tannic acid potently inhibits tumor cell proteasome activity, increases p27 and Bax expression, and induces G1 arrest and apoptosis. Cancer Epidemiol Biomarkers Prev. 2001;10:1083-1088. Ni, L, Feng Y, Wan H, Ma Q, Fan L, Qian Y, Li Q, Xiang Y, Gao B. Angiotensin-(1-7) inhibits the migration and invasion of A549 human lung adenocarcinoma cells through inactivation of the PI3K/Akt and MAPK signaling pathways. Oncol Rep. 2012;27:783-790. Orrenius, S. Reactive oxygen species in mitochondria-mediated cell death. Drug Metab Rev. 2007;39:443-455. Oyadomari, S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11:381-389. Pan, MH, Ghai G, Ho CT. Food bioactives, apoptosis, and cancer. Mol Nutr Food Res. 2008;52:43-52. Pentenero, M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck. 2005;27:1080-1091. Perez, EA. Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther. 2009;8:2086-2095. Petronilli, V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P, Di Lisa F. Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J. 1999;76:725-734. Pitchakarn, P, Suzuki S, Ogawa K, Pompimon W, Takahashi S, Asamoto M, Limtrakul P, Shirai T. Kuguacin J, a triterpeniod from Momordica charantia leaf, modulates the progression of androgen-independent human prostate cancer cell line, PC3. Food Chem Toxicol. 2012;50:840-847. Pozo-Guisado, E, Merino JM, Mulero-Navarro S, Lorenzo-Benayas MJ, Centeno F, Alvarez-Barrientos A, Fernandez-Salguero PM. Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. Int J Cancer. 2005;115:74-84. Pui, CH, Jeha S. New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov. 2007;6:149-165. Quan, Z, Gu J, Dong P, Lu J, Wu X, Wu W, Fei X, Li S, Wang Y, Wang J, Liu Y. Reactive oxygen species-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to cirsimaritin-induced apoptosis in human gallbladder carcinoma GBC-SD cells. Cancer Lett. 2010;295:252-259. Rao, RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 2004;11:372-380. Ripamonti, M, Capolongo L, Melegaro G, Gornati C, Bargiotti A, Caruso M, Grandi M, Suarato A. Morpholinylanthracyclines: cytotoxicity and antitumor activity of differently modified derivatives. Invest New Drugs. 1996;14:139-146. Rosenthal, EL, Matrisian LM. Matrix metalloproteases in head and neck cancer. Head Neck. 2006;28:639-648. Sakoe, Y, Sakoe K, Kirito K, Ozawa K, Komatsu N. FOXO3A as a key molecule for all-trans retinoic acid-induced granulocytic differentiation and apoptosis in acute promyelocytic leukemia. Blood. 2010;115:3787-3795. Sanjiv, K, Su TL, Suman S, Kakadiya R, Lai TC, Wang HY, Hsiao M, Lee TC. The novel DNA alkylating agent BO-1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models. Int J Cancer. 2012;130:1440-1450. Sano, D, Myers JN. Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev. 2007;26:645-662. Sitaresmi, MN, Mostert S, Purwanto I, Gundy CM, Sutaryo, Veerman AJ. Chemotherapy-related side effects in childhood acute lymphoblastic leukemia in indonesia: parental perceptions. J Pediatr Oncol Nurs. 2009;26:198-207. Sommer, G, Rossa C, Chi AC, Neville BW, Heise T. Implication of RNA-binding protein La in proliferation, migration and invasion of lymph node-metastasized hypopharyngeal SCC cells. PLoS One. 2011;6:e25402. Sporn, MB, Suh N. Chemoprevention of cancer. Carcinogenesis. 2000;21:525-530. Stahnke, K, Eckhoff S, Mohr A, Meyer LH, Debatin KM. Apoptosis induction in peripheral leukemia cells by remission induction treatment in vivo: selective depletion and apoptosis in a CD34+ subpopulation of leukemia cells. Leukemia. 2003;17:2130-2139. Sun, Q, Sakaida T, Yue W, Gollin SM, Yu J. Chemosensitization of head and neck cancer cells by PUMA. Mol Cancer Ther. 2007;6:3180-3188. Troeberg, L, Nagase H. Zymography of metalloproteinases. Curr Protoc Protein Sci. 2004;Chapter 21:Unit 21 15. Tseng, MY, Liu SY, Chen HR, Wu YJ, Chiu CC, Chan PT, Chiang WF, Liu YC, Lu CY, Jou YS, Chen JY. Serine protease inhibitor (SERPIN) B1 promotes oral cancer cell motility and is over-expressed in invasive oral squamous cell carcinoma. Oral Oncol. 2009;45:771-776. Tsou, MF, Peng CT, Shih MC, Yang JS, Lu CC, Chiang JH, Wu CL, Lin JP, Lo C, Fan MJ, Chung JG. Benzyl isothiocyanate inhibits murine WEHI-3 leukemia cells in vitro and promotes phagocytosis in BALB/c mice in vivo. Leuk Res. 2009;33:1505-1511. Wagner, EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9:537-549. Wang, JH, Manning BJ, Wu QD, Blankson S, Bouchier-Hayes D, Redmond HP. Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J Immunol. 2003;170:795-804. Wang, LG, Liu XM, Kreis W, Budman DR. The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol. 1999;44:355-361. Wang, SW, Pan SL, Peng CY, Huang DY, Tsai AC, Chang YL, Guh JH, Kuo SC, Lee KH, Teng CM. CHM-1 inhibits hepatocyte growth factor-induced invasion of SK-Hep-1 human hepatocellular carcinoma cells by suppressing matrix metalloproteinase-9 expression. Cancer Lett. 2007;257:87-96. Wang, TP, Shu CH, Fang SC, Huang RF. Folate deprivation enhanced invasiveness of human colon cancer cells mediated by activation of sonic hedgehog signaling through promoter hypomethylation and cross-action with transcription nuclear factor-kappa B pathway. Carcinogenesis. 2012. Weisberg, E, Catley L, Kujawa J, Atadja P, Remiszewski S, Fuerst P, Cavazza C, Anderson K, Griffin JD. Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo. Leukemia. 2004;18:1951-1963. Wolfe, JF, Rathman TL, Sleevi MC, Campbell JA, Greenwood TD. Synthesis and anticonvulsant activity of some new 2-substituted 3-aryl-4(3H)-quinazolinones. J Med Chem. 1990;33:161-166. Wu, CL, Huang AC, Yang JS, Liao CL, Lu HF, Chou ST, Ma CY, Hsia TC, Ko YC, Chung JG. Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC)-mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of caspase-3, mitochondria dysfunction and nitric oxide (NO) in human osteogenic sarcoma U-2 OS cells. J Orthop Res. 2011a;29:1199-1209. Wu, PP, Liu KC, Huang WW, Ma CY, Lin H, Yang JS, Chung JG. Triptolide induces apoptosis in human adrenal cancer NCI-H295 cells through a mitochondrial-dependent pathway. Oncol Rep. 2011b;25:551-557. Wu, SH, Hang LW, Yang JS, Chen HY, Lin HY, Chiang JH, Lu CC, Yang JL, Lai TY, Ko YC, Chung JG. Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways. Anticancer Res. 2010;30:2125-2133. Wu, YC, Hour MJ, Leung WC, Wu CY, Liu WZ, Chang YH, Lee HZ. 2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone inhibits skin cancer M21 cell proliferation through aberrant expression of microtubules and the cell cycle. J Pharmacol Exp Ther. 2011c;338:942-951. Xing, X, Liu V, Xia W, Stephens LC, Huang L, Lopez-Berestein G, Hung MC. Safety studies of the intraperitoneal injection of E1A--liposome complex in mice. Gene Ther. 1997;4:238-243. Yang, HL, Kuo YH, Tsai CT, Huang YT, Chen SC, Chang HW, Lin E, Lin WH, Hseu YC. Anti-metastatic activities of Antrodia camphorata against human breast cancer cells mediated through suppression of the MAPK signaling pathway. Food Chem Toxicol. 2011;49:290-298. Yang, JS, Hour MJ, Huang WW, Lin KL, Kuo SC, Chung JG. MJ-29 inhibits tubulin polymerization, induces mitotic arrest, and triggers apoptosis via cyclin-dependent kinase 1-mediated Bcl-2 phosphorylation in human leukemia U937 cells. J Pharmacol Exp Ther. 2010;334:477-488. Yang, JS, Hour MJ, Kuo SC, Huang LJ, Lee MR. Selective induction of G2/M arrest and apoptosis in HL-60 by a potent anticancer agent, HMJ-38. Anticancer Res. 2004;24:1769-1778. Yang, JS, Kok LF, Lin YH, Kuo TC, Yang JL, Lin CC, Chen GW, Huang WW, Ho HC, Chung JG. Diallyl disulfide inhibits WEHI-3 leukemia cells in vivo. Anticancer Res. 2006;26:219-225. Yu, D, Jing T, Liu B, Yao J, Tan M, McDonnell TJ, Hung MC. Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase. Mol Cell. 1998;2:581-591. Yu, FS, Yang JS, Yu CS, Lu CC, Chiang JH, Lin CW, Chung JG. Safrole induces apoptosis in human oral cancer HSC-3 cells. J Dent Res. 2011;90:168-174. Zhao, M, Sano D, Pickering CR, Jasser SA, Henderson YC, Clayman GL, Sturgis EM, Ow TJ, Lotan R, Carey TE, Sacks PG, Grandis JR, Sidransky D, Heldin NE, Myers JN. Assembly and initial characterization of a panel of 85 genomically validated cell lines from diverse head and neck tumor sites. Clin Cancer Res. 2011;17:7248-7264. Zhou, GB, Kang H, Wang L, Gao L, Liu P, Xie J, Zhang FX, Weng XQ, Shen ZX, Chen J, Gu LJ, Yan M, Zhang DE, Chen SJ, Wang ZY, Chen Z. Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood. 2007;109:3441-3450. Zhou, HY, Wong AS. Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells. Endocrinology. 2006;147:2557-2566. Zhu, GY, Li YW, Tse AK, Hau DK, Leung CH, Yu ZL, Fong WF. 20(S)-Protopanaxadiol, a metabolite of ginsenosides, induced cell apoptosis through endoplasmic reticulum stress in human hepatocarcinoma HepG2 cells. Eur J Pharmacol. 2011;668:88-98. Zucker, S, Cao J. Measurement of matrix metalloproteinases in serum of patients with melanoma: snarled in technical pitfalls. Clin Cancer Res. 2005;11:5069-5070.
先前的研究已證實顯示2-phenyl 6-pyrrolidinyl-4-quinazolinone衍生物具有抗癌活性和生物反應。其中,MJ-29與HMJ-38為二者最具潛力的新合成化合物,然而其抗癌活性機轉既不清楚也無得到很好的釐清。在本篇論文中,我們試圖探討在離體外和活體中抗血癌與口腔癌的作用與效果。在第一章中,我們著重於新穎化合物MJ-29在離體外骨髓單核細胞性小鼠血癌WEHI-3細胞中探討其對內質網壓力和粒線體依賴性細胞凋亡的影響,並推測MJ-29可能影響原位移植誘導的血癌小鼠。在第二章,其研究目標在探索MJ-29對於人類口腔鱗狀細胞癌CAL 27細胞的抗轉移作用的影響,並確認與發掘其相關分子機轉。在第三章中,探討另一新合成和具抗有絲分裂的化合物HMJ-38對於其標的與確切的機轉試驗,我們假設HMJ-38可能敏感化離體外CAL 27細胞的凋亡與其抑制裸小鼠活體上異種移植腫瘤的生長。在此研究中,我們證實發現在MJ-29處理的WEHI-3細胞離體試驗中藉由透過內在路徑與內質網壓力訊息傳遞誘導產生細胞凋亡現象;引人注目的是MJ-29抗血癌反應有在活體試驗血癌小鼠中被觀察到。接著,我們更發現MJ-29透過下調控基質金屬蛋白酶-2/-9(MMP-2/-9)在人類口腔鱗癌CAL 27細胞中能夠抑制細胞黏附、侵襲與移行;且磷酸化AKT和MAPK訊號路徑蛋白可協同參與涉及遭MJ-29抑制所影響的轉移必需步驟。最後,我們的研究提供HMJ-38所引起的CAL 27細胞G2/M期停滯與凋亡的證據與腹腔注射HMJ-38可抑制裸小鼠上CAL 27異種移植腫瘤的生長。總體而言,我們提出MJ-29 與HMJ-38擁有對抗血癌和口腔癌的潛力與治療價值的新發現和反應,再者二者化合物也許未來足以當作具有潛在的治療方式。

The previous studies have demonstrated that 2-phenyl 6-pyrrolidinyl-4-quinazolinone derivatives exhibited antitumor actions and biological responses. Among them, both of the most potent newly synthesized compounds, 6-pyrrolidinyl-2-(2-hydroxyphenyl)-4-quinazolinone (MJ-29) and 6-pyrrolidinyl- 2-(3-Methoxyphenyl)-4-quinazolinone (HMJ-38) for their mechanisms underlying anticancer activities remain unclear and have not been well clarified. In this dissertation, we attempt to investigate anti-leukemia and anti-oral cancer effects in vitro and in vivo. In the chapter 1, we focused on the in vitro effects of MJ-29 on ER stress and mitochondria-dependent apoptotic death in murine myelomonocytic leukemia WEHI-3 cells, and to hypothesize that MJ-29 might fully impair the orthotopic leukemic mice. In the chapter 2, the objective of current study was explored the effects of the novel compound MJ-29 on anti-metastatic actions of human oral squamous cell carcinoma (OSCC) CAL 27 cells and to verify the underlying related molecular mechanisms in this event. In the chapter 3, this study investigated the newly synthesized and anti-mitotic compound, HMJ-38 addressing its target and precise mechanism of actions. We hypothesized that HMJ-38 might sensitize apoptotic death of CAL 27 cells in vitro and inhibit xenografts tumor growth in vivo. In my Ph.D. study, we found that the induction of cell death in MJ-29-treated WEHI-3 cells has been proven by an assessment of apoptosis in vitro culture through intrinsic apoptotic pathway and ER stress signaling. Strikingly, anti-leukemia responses by MJ-29 were observed in leukemic mice in vivo. We further demonstrated that MJ-29 is capable of inhibiting cell adhesion, invasion and migration through the down-regulation of MMP-2 and MMP-9 in human OSCC CAL 27 cells. Also, the phosphorylation of AKT and MAPK signaling pathway proteins may be coordinately involved in the inhibitory effect on these essential steps of metastasis by MJ-29. Finally, our study provides evidence for G2/M phase arrest and apoptosis caused by HMJ-38 in CAL 27 cells, and HMJ-38 by intraperitoneal administration suppressed CAL 27 xenografts tumor growth in nude mice. Overall, we presented the novel findings that MJ-29 and HMJ-38 possess a potent therapeutic value for use against leukemia and oral cancer in response to cell-fate decision, and the efficacy of both compounds might be sufficient to investigate the potential of treatment in the future.
其他識別: U0005-0807201214440000
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