Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/51954
標題: Chemopreventive effects of apo-8'-lycopenal, an enzymatic metabolite of lycopene: activation of Nrf2-ARE transcriptional system, anti-metastasis and anti-angiogenesis
茄紅素酵素代謝產物apo-8’-lycopenal的化學預防作用:活化Nrf2-ARE轉錄系統、抑制癌細胞轉移以及抑制血管新生
作者: Yang, Chih-Min
楊智閔
關鍵字: Angiogenesis
血管新生
Apo-8'-lycopenal
Lycopene
metastasis
Nrf2-ARE transcription system
茄紅素
轉移
類紅血球衍生生長因子-抗氧化反應元件轉錄系統
出版社: 食品暨應用生物科技學系所
引用: Chapter 1 [1] Yonekura, L., Nagao, A., Intestinal absorption of dietary carotenoids. Mol Nutr Food Res 2007, 51, 107-115. [2] Nishino, H., Murakosh, M., Ii, T., Takemura, M., et al., Carotenoids in cancer chemoprevention. Cancer Metastasis Rev 2002, 21, 257-264. [3] Goodman, D. S., Huang, H. S., Biosynthesis of Vitamin a with Rat Intestinal Enzymes. Science 1965, 149, 879-880. [4] Olson, J. A., Hayaishi, O., The enzymatic cleavage of beta-carotene into vitamin A by soluble enzymes of rat liver and intestine. Proc Natl Acad Sci U S A 1965, 54, 1364-1370. [5] Hessel, S., Eichinger, A., Isken, A., Amengual, J., et al., CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice. J Biol Chem 2007, 282, 33553-33561. [6] Kiefer, C., Hessel, S., Lampert, J. M., Vogt, K., et al., Identification and characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A. J Biol Chem 2001, 276, 14110-14116. [7] Olson, J. A., Krinsky, N. I., Introduction: the colorful, fascinating world of the carotenoids: important physiologic modulators. FASEB J 1995, 9, 1547-1550. [8] van Breemen, R. B., Pajkovic, N., Multitargeted therapy of cancer by lycopene. Cancer Lett 2008, 269, 339-351. [9] Clinton, S. K., Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev 1998, 56, 35-51. [10] Stahl, W., Sies, H., Lycopene: a biologically important carotenoid for humans? Arch Biochem Biophys 1996, 336, 1-9. [11] Stahl, W., Schwarz, W., Sundquist, A. R., Sies, H., cis-trans isomers of lycopene and beta-carotene in human serum and tissues. Arch Biochem Biophys 1992, 294, 173-177. [12] Yan, W., Jang, G. F., Haeseleer, F., Esumi, N., et al., Cloning and characterization of a human beta,beta-carotene-15,15''-dioxygenase that is highly expressed in the retinal pigment epithelium. Genomics 2001, 72, 193-202. [13] Lindqvist, A., Andersson, S., Biochemical properties of purified recombinant human beta-carotene 15,15''-monooxygenase. J Biol Chem 2002, 277, 23942-23948. [14] Nagao, A., Olson, J. A., Enzymatic formation of 9-cis, 13-cis, and all-trans retinals from isomers of beta-carotene. FASEB J 1994, 8, 968-973. [15] Mein, J. R., Lian, F., Wang, X. D., Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev 2008, 66, 667-683. [16] Hu, K. Q., Liu, C., Ernst, H., Krinsky, N. I., et al., The biochemical characterization of ferret carotene-9'',10''-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. J Biol Chem 2006, 281, 19327-19338. [17] Britton, G., Structure and properties of carotenoids in relation to function. FASEB J 1995, 9, 1551-1558. [18] Di Mascio, P., Kaiser, S., Sies, H., Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989, 274, 532-538. [19] Krinsky, N. I., The antioxidant and biological properties of the carotenoids. Ann N Y Acad Sci 1998, 854, 443-447. [20] Conn, P. F., Schalch, W., Truscott, T. G., The singlet oxygen and carotenoid interaction. J Photochem Photobiol B 1991, 11, 41-47. [21] Muzandu, K., Ishizuka, M., Sakamoto, K. Q., Shaban, Z., et al., Effect of lycopene and beta-carotene on peroxynitrite-mediated cellular modifications. Toxicol Appl Pharmacol 2006, 215, 330-340. [22] Muzandu, K., El Bohi, K., Shaban, Z., Ishizuka, M., et al., Lycopene and beta-carotene ameliorate catechol estrogen-mediated DNA damage. Jpn J Vet Res 2005, 52, 173-184. [23] Park, Y. O., Hwang, E. S., Moon, T. W., The effect of lycopene on cell growth and oxidative DNA damage of Hep3B human hepatoma cells. Biofactors 2005, 23, 129-139. [24] Ben-Dor, A., Steiner, M., Gheber, L., Danilenko, M., et al., Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther 2005, 4, 177-186. [25] Goo, Y. A., Li, Z., Pajkovic, N., Shaffer, S., et al., Systematic investigation of lycopene effects in LNCaP cells by use of novel large-scale proteomic analysis software. Proteomics Clin Appl 2007, 1, 513-523. [26] Breinholt, V., Lauridsen, S. T., Daneshvar, B., Jakobsen, J., Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat. Cancer Lett 2000, 154, 201-210. [27] Huang, C. S., Shih, M. K., Chuang, C. H., Hu, M. L., Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. J Nutr 2005, 135, 2119-2123. [28] Huang, C. S., Fan, Y. E., Lin, C. Y., Hu, M. L., Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1. J Nutr Biochem 2007, 18, 449-456. [29] Hwang, E. S., Lee, H. J., Inhibitory effects of lycopene on the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells. Exp Biol Med (Maywood) 2006, 231, 322-327. [30] Huang, C. S., Liao, J. W., Hu, M. L., Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice. J Nutr 2008, 138, 538-543. [31] Sahin, M., Sahin, E., Gumuslu, S., Effects of lycopene and apigenin on human umbilical vein endothelial cells in vitro under angiogenic stimulation. Acta Histochem 2011, doi:10.1016/j.acthis.2011.03.004. [32] Fornelli, F., Leone, A., Verdesca, I., Minervini, F., Zacheo, G., The influence of lycopene on the proliferation of human breast cell line (MCF-7). Toxicol In Vitro 2007, 21, 217-223. [33] Gunasekera, R. S., Sewgobind, K., Desai, S., Dunn, L., et al., Lycopene and lutein inhibit proliferation in rat prostate carcinoma cells. Nutr Cancer 2007, 58, 171-177. [34] Barber, N. J., Zhang, X., Zhu, G., Pramanik, R., et al., Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic Dis 2006, 9, 407-413. [35] Salman, H., Bergman, M., Djaldetti, M., Bessler, H., Lycopene affects proliferation and apoptosis of four malignant cell lines. Biomed Pharmacother 2007, 61, 366-369. [36] Hantz, H. L., Young, L. F., Martin, K. R., Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med (Maywood) 2005, 230, 171-179. [37] Tang, L., Jin, T., Zeng, X., Wang, J. S., Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr 2005, 135, 287-290. [38] Siler, U., Herzog, A., Spitzer, V., Seifert, N., et al., Lycopene effects on rat normal prostate and prostate tumor tissue. J Nutr 2005, 135, 2050S-2052S. [39] Nagasawa, H., Mitamura, T., Sakamoto, S., Yamamoto, K., Effects of lycopene on spontaneous mammary tumour development in SHN virgin mice. Anticancer Res 1995, 15, 1173-1178. [40] Giovannucci, E., Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 1999, 91, 317-331. [41] Giovannucci, E., Rimm, E. B., Liu, Y., Stampfer, M. J., Willett, W. C., A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 2002, 94, 391-398. [42] Sicilia, T., Bub, A., Rechkemmer, G., Kraemer, K., et al., Novel lycopene metabolites are detectable in plasma of preruminant calves after lycopene supplementation. J Nutr 2005, 135, 2616-2621. [43] Gajic, M., Zaripheh, S., Sun, F., Erdman, J. W., Jr., Apo-8''-lycopenal and apo-12''-lycopenal are metabolic products of lycopene in rat liver. J Nutr 2006, 136, 1552-1557. [44] Kim, S. J., Nara, E., Kobayashi, H., Terao, J., Nagao, A., Formation of cleavage products by autoxidation of lycopene. Lipids 2001, 36, 191-199. [45] Ferreira, A. L., Yeum, K. J., Russell, R. M., Krinsky, N. I., Tang, G., Enzymatic and oxidative metabolites of lycopene. J Nutr Biochem 2003, 14, 531-540. [46] Caris-Veyrat, C., Schmid, A., Carail, M., Bohm, V., Cleavage products of lycopene produced by in vitro oxidations: characterization and mechanisms of formation. J Agric Food Chem 2003, 51, 7318-7325. [47] Lian, F., Wang, X. D., Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. Int J Cancer 2008, 123, 1262-1268. [48] Kopec, R. E., Riedl, K. M., Harrison, E. H., Curley, R. W., Jr., et al., Identification and quantification of apo-lycopenals in fruits, vegetables, and human plasma. J Agric Food Chem 2010, 58, 3290-3296. [49] Ford, N. A., Elsen, A. C., Zuniga, K., Lindshield, B. L., Erdman, J. W., Jr., Lycopene and apo-12''-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutr Cancer 2011, 63, 256-263. [50] Lian, F., Smith, D. E., Ernst, H., Russell, R. M., Wang, X. D., Apo-10''-lycopenoic acid inhibits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo. Carcinogenesis 2007, 28, 1567-1574. [51] Linnewiel, K., Ernst, H., Caris-Veyrat, C., Ben-Dor, A., et al., Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system. Free Radic Biol Med 2009, 47, 659-667. [52] Hwang, E. S., Bowen, P. E., Can the consumption of tomatoes or lycopene reduce cancer risk? Integr Cancer Ther 2002, 1, 121-132; discussion 132. [53] Krinsky, N. I., Johnson, E. J., Carotenoid actions and their relation to health and disease. Mol Aspects Med 2005, 26, 459-516. [54] Giudice, A., Montella, M., Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. Bioessays 2006, 28, 169-181. [55] Ford, N. A., Erdman Jr, J. W., Investigation of Apo-lycopenals in DU145 & LNCaP Cells. The FASEB Journal 2007, 21, A1088. [56] Wattenberg, L. W., Chemoprophylaxis of carcinogenesis: a review. Cancer Res 1966, 26, 1520-1526. [57] Sporn, M. B., Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 1976, 36, 2699-2702. [58] Surh, Y. J., Kundu, J. K., Na, H. K., Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008, 74, 1526-1539. [59] Surh, Y. J., Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003, 3, 768-780. [60] Hong, F., Freeman, M. L., Liebler, D. C., Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 2005, 18, 1917-1926. [61] Thangapazham, R. L., Sharma, A., Maheshwari, R. K., Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J 2006, 8, E443-449. [62] Wu, C. C., Hsu, M. C., Hsieh, C. W., Lin, J. B., et al., Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci 2006, 78, 2889-2897. [63] Tanigawa, S., Fujii, M., Hou, D. X., Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 2007, 42, 1690-1703. [64] Chen, C. Y., Jang, J. H., Li, M. H., Surh, Y. J., Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem Biophys Res Commun 2005, 331, 993-1000. [65] Weinstat-Saslow, D., Steeg, P. S., Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. FASEB J 1994, 8, 401-407. [66] Steeg, P. S., Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006, 12, 895-904. [67] Deryugina, E. I., Quigley, J. P., Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 2006, 25, 9-34. [68] Liotta, L. A., Tryggvason, K., Garbisa, S., Hart, I., et al., Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980, 284, 67-68. [69] Parmo-Cabanas, M., Molina-Ortiz, I., Matias-Roman, S., Garcia-Bernal, D., et al., Role of metalloproteinases MMP-9 and MT1-MMP in CXCL12-promoted myeloma cell invasion across basement membranes. J Pathol 2006, 208, 108-118. [70] Bjorklund, M., Koivunen, E., Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 2005, 1755, 37-69. [71] Sier, C. F., Kubben, F. J., Ganesh, S., Heerding, M. M., et al., Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer 1996, 74, 413-417. [72] Liabakk, N. B., Talbot, I., Smith, R. A., 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. [73] Hidalgo, M., Eckhardt, S. G., Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001, 93, 178-193. [74] Han, X., Zhang, H., Jia, M., Han, G., Jiang, W., Expression of TIMP-3 gene by construction of a eukaryotic cell expression vector and its role in reduction of metastasis in a human breast cancer cell line. Cell Mol Immunol 2004, 1, 308-310. [75] Patterson, M. L., Atkinson, S. J., Knauper, V., Murphy, G., Specific collagenolysis by gelatinase A, MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain. FEBS Lett 2001, 503, 158-162. [76] Bloomston, M., Shafii, A., Zervos, E. E., Rosemurgy, A. S., TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis. J Surg Res 2002, 102, 39-44. [77] Ikenaka, Y., Yoshiji, H., Kuriyama, S., Yoshii, J., et al., Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits tumor growth and angiogenesis in the TIMP-1 transgenic mouse model. Int J Cancer 2003, 105, 340-346. [78] Kawamata, H., Kawai, K., Kameyama, S., Johnson, M. D., et al., Over-expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma. Int J Cancer 1995, 63, 680-687. [79] Libra, M., Scalisi, A., Vella, N., Clementi, S., et al., Uterine cervical carcinoma: role of matrix metalloproteinases (review). Int J Oncol 2009, 34, 897-903. [80] Iwata, H., Kobayashi, S., Iwase, H., Okada, Y., [The expression of MMPs and TIMPs in human breast cancer tissues and importance of their balance in cancer invasion and metastasis]. Nihon Rinsho 1995, 53, 1805-1810. [81] Nobes, C. D., Hall, A., Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 1995, 81, 53-62. [82] Grise, F., Bidaud, A., Moreau, V., Rho GTPases in hepatocellular carcinoma. Biochim Biophys Acta 2009, 1795, 137-151. [83] Kim, T. Y., Vigil, D., Der, C. J., Juliano, R. L., Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility. Cancer Metastasis Rev 2009, 28, 77-83. [84] Keely, P. J., Westwick, J. K., Whitehead, I. P., Der, C. J., Parise, L. V., Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 1997, 390, 632-636. [85] Nikolopoulos, S. N., Blaikie, P., Yoshioka, T., Guo, W., Giancotti, F. G., Integrin beta4 signaling promotes tumor angiogenesis. Cancer Cell 2004, 6, 471-483. [86] Stahl, J. A., Leone, A., Rosengard, A. M., Porter, L., et al., Identification of a second human nm23 gene, nm23-H2. Cancer Res 1991, 51, 445-449. [87] Tannapfel, A., Kockerling, F., Katalinic, A., Wittekind, C., Expression of nm23-H1 predicts lymph node involvement in colorectal carcinoma. Dis Colon Rectum 1995, 38, 651-654. [88] Viel, A., Dall''Agnese, L., Canzonieri, V., Sopracordevole, F., et al., Suppressive role of the metastasis-related nm23-H1 gene in human ovarian carcinomas: association of high messenger RNA expression with lack of lymph node metastasis. Cancer Res 1995, 55, 2645-2650. [89] Nakayama, T., Ohtsuru, A., Nakao, K., Shima, M., et al., Expression in human hepatocellular carcinoma of nucleoside diphosphate kinase, a homologue of the nm23 gene product. J Natl Cancer Inst 1992, 84, 1349-1354. [90] Liu, F., Zhang, Y., Zhang, X. Y., Chen, H. L., Transfection of the nm23-H1 gene into human hepatocarcinoma cell line inhibits the expression of sialyl Lewis X, alpha1,3 fucosyltransferase VII, and metastatic potential. J Cancer Res Clin Oncol 2002, 128, 189-196. [91] Leone, A., Flatow, U., King, C. R., Sandeen, M. A., et al., Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 1991, 65, 25-35. [92] Leone, A., Flatow, U., VanHoutte, K., Steeg, P. S., Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity. Oncogene 1993, 8, 2325-2333. [93] Cheng, S., Alfonso-Jaume, M. A., Mertens, P. R., Lovett, D. H., Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). Biochem J 2002, 366, 807-816. [94] Murakami, M., Meneses, P. I., Lan, K., Robertson, E. S., The suppressor of metastasis Nm23-H1 interacts with the Cdc42 Rho family member and the pleckstrin homology domain of oncoprotein Dbl-1 to suppress cell migration. Cancer Biol Ther 2008, 7, 677-688. [95] Miyazaki, T., Kato, H., Nakajima, M., Sohda, M., et al., FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer 2003, 89, 140-145. [96] Yam, J. W., Tse, E. Y., Ng, I. O., Role and significance of focal adhesion proteins in hepatocellular carcinoma. J Gastroenterol Hepatol 2009, 24, 520-530. [97] Schlaepfer, D. D., Hanks, S. K., Hunter, T., van der Geer, P., Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1994, 372, 786-791. [98] Brader, S., Eccles, S. A., Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004, 90, 2-8. [99] Meng, X. N., Jin, Y., Yu, Y., Bai, J., et al., Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer 2009, 101, 327-334. [100] Wright, T. J., Leach, L., Shaw, P. E., Jones, P., Dynamics of vascular endothelial-cadherin and beta-catenin localization by vascular endothelial growth factor-induced angiogenesis in human umbilical vein cells. Exp Cell Res 2002, 280, 159-168. [101] Izuta, H., Shimazawa, M., Tsuruma, K., Araki, Y., et al., Bee products prevent VEGF-induced angiogenesis in human umbilical vein endothelial cells. BMC Complement Altern Med 2009, 9, 45. [102] Karamysheva, A. F., Mechanisms of angiogenesis. Biochemistry (Mosc) 2008, 73, 751-762. [103] Folkman, J., What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990, 82, 4-6. [104] Ferrara, N., Kerbel, R. S., Angiogenesis as a therapeutic target. Nature 2005, 438, 967-974. [105] Ferrara, N., Alitalo, K., Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 1999, 5, 1359-1364. [106] Meyer, M., Clauss, M., Lepple-Wienhues, A., Waltenberger, J., et al., A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 1999, 18, 363-374. [107] Bischoff, J., Approaches to studying cell adhesion molecules in angiogenesis. Trends Cell Biol 1995, 5, 69-74. [108] Sang, Q. X., Complex role of matrix metalloproteinases in angiogenesis. Cell Res 1998, 8, 171-177. Chapter 2 [1] Sporn, M. B., Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 1976, 36, 2699-2702. [2] Surh, Y. J., Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003, 3, 768-780. [3] Surh, Y. J., NF-kappa B and Nrf2 as potential chemopreventive targets of some anti-inflammatory and antioxidative phytonutrients with anti-inflammatory and antioxidative activities. Asia Pac J Clin Nutr 2008, 17 Suppl 1, 269-272. [4] Gopalakrishnan, A., Tony Kong, A. N., Anticarcinogenesis by dietary phytochemicals: cytoprotection by Nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-kappa B and AP-1 in abnormal cancer cells. Food Chem Toxicol 2008, 46, 1257-1270. [5] Surh, Y. J., Kundu, J. K., Na, H. K., Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008, 74, 1526-1539. [6] Marrot, L., Jones, C., Perez, P., Meunier, J. R., The significance of Nrf2 pathway in (photo)-oxidative stress response in melanocytes and keratinocytes of the human epidermis. Pigment Cell Melanoma Res 2008, 21, 79-88. [7] Giudice, A., Montella, M., Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. Bioessays 2006, 28, 169-181. [8] Lee, J. S., Surh, Y. J., Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 2005, 224, 171-184. [9] Alam, J., Stewart, D., Touchard, C., Boinapally, S., et al., Nrf2, a Cap''n''Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 1999, 274, 26071-26078. [10] Hong, F., Freeman, M. L., Liebler, D. C., Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 2005, 18, 1917-1926. [11] Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., et al., Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 2002, 62, 5196-5203. [12] Keum, Y. S., Yu, S., Chang, P. P., Yuan, X., et al., Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells. Cancer Res 2006, 66, 8804-8813. [13] McMahon, M., Itoh, K., Yamamoto, M., Chanas, S. A., et al., The Cap''n''Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 2001, 61, 3299-3307. [14] Thangapazham, R. L., Sharma, A., Maheshwari, R. K., Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J 2006, 8, E443-449. [15] Shen, G., Xu, C., Hu, R., Jain, M. R., et al., Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin. Mol Cancer Ther 2006, 5, 39-51. [16] Balogun, E., Hoque, M., Gong, P., Killeen, E., et al., Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 2003, 371, 887-895. [17] Nishinaka, T., Ichijo, Y., Ito, M., Kimura, M., et al., Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element. Toxicol Lett 2007, 170, 238-247. [18] Farombi, E. O., Shrotriya, S., Na, H. K., Kim, S. H., Surh, Y. J., Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food Chem Toxicol 2008, 46, 1279-1287. [19] Wu, C. C., Hsu, M. C., Hsieh, C. W., Lin, J. B., et al., Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci 2006, 78, 2889-2897. [20] Andreadi, C. K., Howells, L. M., Atherfold, P. A., Manson, M. M., Involvement of Nrf2, p38, B-Raf, and nuclear factor-kappaB, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols. Mol Pharmacol 2006, 69, 1033-1040. [21] Na, H. K., Kim, E. H., Jung, J. H., Lee, H. H., et al., (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch Biochem Biophys 2008, 476, 171-177. [22] Park, O. J., Surh, Y. J., Chemopreventive potential of epigallocatechin gallate and genistein: evidence from epidemiological and laboratory studies. Toxicol Lett 2004, 150, 43-56. [23] Hanneken, A., Lin, F. F., Johnson, J., Maher, P., Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci 2006, 47, 3164-3177. [24] Tanigawa, S., Fujii, M., Hou, D. X., Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 2007, 42, 1690-1703. [25] Yao, P., Nussler, A., Liu, L., Hao, L., et al., Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol 2007, 47, 253-261. [26] Chen, C. Y., Jang, J. H., Li, M. H., Surh, Y. J., Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem Biophys Res Commun 2005, 331, 993-1000. [27] Kode, A., Rajendrasozhan, S., Caito, S., Yang, S. R., et al., Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. American Journal of Physiology-Lung Cellular and Molecular Physiology 2008, 294, L478. [28] Huang, C. S., Shih, M. K., Chuang, C. H., Hu, M. L., Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. J Nutr 2005, 135, 2119-2123. [29] Huang, C. S., Fan, Y. E., Lin, C. Y., Hu, M. L., Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1. J Nutr Biochem 2007, 18, 449-456. [30] Huang, C. S., Liao, J. W., Hu, M. L., Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice. J Nutr 2008, 138, 538-543. [31] Sahin, M., Sahin, E., Gumuslu, S., Effects of lycopene and apigenin on human umbilical vein endothelial cells in vitro under angiogenic stimulation. Acta Histochem. [32] Salman, H., Bergman, M., Djaldetti, M., Bessler, H., Lycopene affects proliferation and apoptosis of four malignant cell lines. Biomed Pharmacother 2007, 61, 366-369. [33] Hantz, H. L., Young, L. F., Martin, K. R., Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med (Maywood) 2005, 230, 171-179. [34] Hwang, E. S., Bowen, P. E., Cell cycle arrest and induction of apoptosis by lycopene in LNCaP human prostate cancer cells. J Med Food 2004, 7, 284-289. [35] Yang, C. M., Lu, I. H., Chen, H. Y., Hu, M. L., Lycopene inhibits the proliferation of androgen-dependent human prostate tumor cells through activation of PPARgamma-LXRalpha-ABCA1 pathway. J Nutr Biochem. [36] Hwang, E. S., Bowen, P. E., Can the consumption of tomatoes or lycopene reduce cancer risk? Integr Cancer Ther 2002, 1, 121-132; discussion 132. [37] Ben-Dor, A., Steiner, M., Gheber, L., Danilenko, M., et al., Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther 2005, 4, 177-186. [38] Bhuvaneswari, V., Velmurugan, B., Balasenthil, S., Ramachandran, C. R., Nagini, S., Chemopreventive efficacy of lycopene on 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Fitoterapia 2001, 72, 865-874. [39] Ford, N. A., Elsen, A. C., Zuniga, K., Lindshield, B. L., Erdman, J. W., Jr., Lycopene and apo-12''-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutr Cancer, 63, 256-263. [40] Lian, F., Smith, D. E., Ernst, H., Russell, R. M., Wang, X. D., Apo-10''-lycopenoic acid inhibits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo. Carcinogenesis 2007, 28, 1567-1574. [41] Lian, F., Wang, X. D., Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. Int J Cancer 2008, 123, 1262-1268. [42] Mein, J. R., Lian, F., Wang, X. D., Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev 2008, 66, 667-683. [43] Linnewiel, K., Ernst, H., Caris-Veyrat, C., Ben-Dor, A., et al., Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system. Free Radic Biol Med 2009, 47, 659-667. [44] Gajic, M., Zaripheh, S., Sun, F., Erdman, J. W., Jr., Apo-8''-lycopenal and apo-12''-lycopenal are metabolic products of lycopene in rat liver. J Nutr 2006, 136, 1552-1557. [45] Kopec, R. E., Riedl, K. M., Harrison, E. H., Curley, R. W., Jr., et al., Identification and quantification of apo-lycopenals in fruits, vegetables, and human plasma. J Agric Food Chem, 58, 3290-3296. [46] Musonda, C. A., Helsby, N., Chipman, J. K., Effects of quercetin on drug metabolizing enzymes and oxidation of 2'',7-dichlorofluorescin in HepG2 cells. Hum Exp Toxicol 1997, 16, 700-708. [47] Feng, Q., Torii, Y., Uchida, K., Nakamura, Y., et al., Black tea polyphenols, theaflavins, prevent cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 1A1 in cell cultures. J Agric Food Chem 2002, 50, 213-220. [48] Ramos, S., Alia, M., Bravo, L., Goya, L., Comparative effects of food-derived polyphenols on the viability and apoptosis of a human hepatoma cell line (HepG2). J Agric Food Chem 2005, 53, 1271-1280. [49] Lin, C. Y., Huang, C. S., Hu, M. L., The use of fetal bovine serum as delivery vehicle to improve the uptake and stability of lycopene in cell culture studies. Br J Nutr 2007, 98, 226-232. [50] Kwak, M. K., Itoh, K., Yamamoto, M., Kensler, T. W., Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 2002, 22, 2883-2892. [51] Kataoka, K., Handa, H., Nishizawa, M., Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold(I) compounds. J Biol Chem 2001, 276, 34074-34081. [52] Stangl, V., Lorenz, M., Meiners, S., Ludwig, A., et al., Long-term up-regulation of eNOS and improvement of endothelial function by inhibition of the ubiquitin-proteasome pathway. FASEB J 2004, 18, 272-279. [53] Kitamuro, T., Takahashi, K., Ogawa, K., Udono-Fujimori, R., et al., Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells. J Biol Chem 2003, 278, 9125-9133. [54] Takahashi, K., Hara, E., Ogawa, K., Kimura, D., et al., Possible implications of the induction of human heme oxygenase-1 by nitric oxide donors. J Biochem 1997, 121, 1162-1168. [55] Nakayama, M., Takahashi, K., Kitamuro, T., Yasumoto, K., et al., Repression of heme oxygenase-1 by hypoxia in vascular endothelial cells. Biochem Biophys Res Commun 2000, 271, 665-671. [56] Pearson, G., Robinson, F., Beers Gibson, T., Xu, B. E., et al., Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 2001, 22, 153-183. [57] Lue, H., Kapurniotu, A., Fingerle-Rowson, G., Roger, T., et al., Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity. Cell Signal 2006, 18, 688-703. [58] Diamond-Stanic, M. K., Marchionne, E. M., Teachey, M. K., Durazo, D. E., et al., Critical role of the transient activation of p38 MAPK in the etiology of skeletal muscle insulin resistance induced by low-level in vitro oxidant stress. Biochem Biophys Res Commun, 405, 439-444. [59] Nandi, D., Tahiliani, P., Kumar, A., Chandu, D., The ubiquitin-proteasome system. J Biosci 2006, 31, 137-155. [60] Su, H., Wang, X., The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective. Cardiovasc Res, 85, 253-262. [61] Murakami, A., Tanaka, T., Lee, J. Y., Surh, Y. J., et al., Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice. Int J Cancer 2004, 110, 481-490. [62] Nakamura, Y., Yoshida, C., Murakami, A., Ohigashi, H., et al., Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes. FEBS Lett 2004, 572, 245-250. [63] Dinkova-Kostova, A. T., Abeygunawardana, C., Talalay, P., Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers. J Med Chem 1998, 41, 5287-5296. [64] Kobayashi, M., Yamamoto, M., Nrf2-Keap1 regulation of cellular defe
摘要: 許多研究指出茄紅素在活體內外可藉由活化類紅血球衍生生長因子nuclear factor erythroid-derived 2-like 2 (Nrf2)-抗氧化反應元件antioxidant response element (ARE)轉錄系統、抑制癌細胞轉移以及抑制血管新生,在癌症化學預防與化學治療作用上扮演重要角色。茄紅素在肝臟中可藉由胡蘿蔔素氧合酶的作用,裂解形成類茄紅素(lycopenoids),例如apo-lycopenal、apo-lycopenol及apo-lycopenoic acid。在這些類茄紅素中,apo-8''-lycopenal存在於人體血漿以及含有茄紅素食物中,為主要的茄紅素代謝產物之一。此外有研究指出茄紅素的化學預防與化學治療作用有部份來自於其代謝產物。 雖然茄紅素及其代謝產物apo-10''-lycopenoic acid已被證實可藉由Nrf2-ARE轉錄系統,而誘導二期抗氧化/解毒酵素,因而具有癌症化學預防作用,然而目前對於apo-8''-lycopenal是否也具有相同效果仍不清楚。因此,我們首先以人類肝癌細胞(HepG2 cells)作為細胞模式,探討apo-8''-lycopenal對於類紅血球衍生生長因子-抗氧化反應元件轉錄系統所調控之二期抗氧化/解毒酵素的影響。結果發現apo-8''-lycopenal (1-10 μM):1) 可顯著增加Nrf2由細胞質轉位到細胞核;2) ARE報導基因的活性;3) Nrf2與ARE結合能力;4) 細胞質中蛋白酶體活性,以及5) 下游二期抗氧化/解毒酵素如第一型血紅素氧化酶(heme oxygenase, HO-1)及NAD(P)H:quinine oxidoreductase 1 (NQO-1)的表現,但會降低細胞質中Kelch-like ECH-associated protein 1 (Keap1)蛋白質表現。利用RNA干擾技術使得Nrf2表現靜默化以及MAPK家族特異性抑制劑PD98059與SB230503,我們發現ERK/p38-Nrf2路徑參與了apo-8''-lycopenal活化HO-1及NQO-1的表現,進而降低細胞內活性氧含量。此外,我們也發現茄紅素在活化Nrf2轉位到細胞核的時間較apo-8''-lycopenal慢,因此我們認為茄紅素的化學預防作用可能有部分來自於其代謝產物apo-8''-lycopenal。 雖然活體內外研究發現茄紅素可抑制腫瘤轉移,但其代謝產物是否也有相同的效果所知甚少。因此我們利用具有高度轉移能力的肝癌SK-Hep-1細胞株作為試驗模式,比較apo-8''-lycopenal (1-10 μM)與茄紅素(10 μM)抑制肝癌細胞轉移的能力,並進一步探討apo-8''-lycopenal的抑制癌細胞轉移分子機制。結果顯示,apo-8''-lycopenal及茄紅素可顯著抑制肝癌細胞侵襲(invasion)與移行(migration),並且在相同濃度下apo-8''-lycopenal抑制效果優於茄紅素。在分子機制上,apo-8''-lycopenal:1) 可顯著降低基質金屬蛋白酶(matrix metalloproteinase, MMP)-2及-9的活性及蛋白質表現;2) 增加抗轉移基因nm23H1及基質金屬蛋白酶內生性抑制劑(tissue inhibitor of matrix metalloproteinase, TIMP)-1及-2的蛋白質表現;3) 抑制癌細胞移行相關蛋白質表現如Rho GTPase以及4) 抑制黏著斑激酶所調控之訊號路徑如ERK/p38及PI3K-Akt路徑。這些結果意味apo-8’-lycopenal具有抑制肝癌細胞轉移的能力,而此抑制效果優於茄紅素,因此我們認為茄紅素的抑制癌細胞轉移的效果可能部份來自於其代謝產物apo-8''-lycopenal。 Apo-8''-lycopenal除了可抑制癌細胞轉移外,我們也發現apo-8''-lycopenal可顯著降低肝癌細胞中血管內皮生長因子(vascular endothelial growth factor, VEGF)的含量。VEGF為內皮細胞特異型分泌性蛋白,在血管新生過程中扮演重要角色。因此我們更進一步探討apo-8''-lycopenal對於血管新生的影響。我們利用離體外法分析法(如大鼠主動脈環),驗證apo-8''-lycopenal抑制血管新生的效果並與茄紅素比較,也利用人類臍靜脈內皮(human umbilical vein endothelial cells, HUVECs)細胞探討apo-8''-lycopenal在抑制血管新生作用上的分子機制。結果顯示,在大鼠主動脈環試驗中,apo-8''-lycopenal可顯著抑制新血管生成,而其抑制效果優於相同濃度的茄紅素。在分子機制上,apo-8''-lycopenal可顯著抑制HUVECs的脈管生成、移行及侵襲作用,而此抑制作用伴隨著向下調節血管內皮生長因子受器(vascular endothelial growth factor receptor, VEGFR)-2所調控之MMP-2活性及向上調節TIMP-2表現。這些結果顯示apo-8''-lycopenal在活體外與離體外具有抑制血管新生活性,而此抑制效果優於茄紅素,因此我們認為茄紅素的抑制血管新生作用可能部分來自於其代謝產物apo-8''-lycopenal。 以上結果意味,apo-8''-lycopenal具有化學預防及化學治療的活性包括活Nrf2-ARE轉錄系統、抑制癌細胞轉移,以及抑制血管新生。此外,茄紅素的化學預防與化學治療活性可能部分來自於其代謝產物apo-8''-lycopenal。本研究提供了茄紅素代謝產物之化學預防與化學治療的相關論證,可作為將來研發化學預防或化學治療試劑的依據。
Several studies have demonstrated the critical roles of lycopene in cancer chemoprevention and chemotherapy, including activation of nuclear factor erythroid-derived 2-like 2 (Nrf2)-antioxidant response element (ARE) transcriptional system, anti-metastasis and anti-angiogenesis both in vitro and in vivo. Lycopene can be cleaved by hepatic carotene-oxygenase to form lycopenoids, such as apo-lycopenal, apo-lycopenol and apo-lycopenoic acid. Among these lycopenoids, apo-8'-lycopenal is one of the major metabolites in rat liver, lycopene-containing food and human plasma. In addition, it has been shown that the chemopreventive and chemotherapeutic activity of lycopene may be attributed, at least in part, to lycopene metabolites. Although lycopene and its metabolite apo-10'-lycopenoic acid have been shown to induce phase II antioxidant/detoxifying enzymes through the activation of Nrf2-ARE transcription system, little is known whether apo-8'-lyocpenal has similar effects. Herein, we first investigated the effect of apo-8'-lycopenal on Nrf2-ARE system-mediated heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO-1) expression in human hepatoma HepG2 cells. We found that apo-8'-lycopenal (1-10 μM) significantly increased nuclear Nrf2 accumulation, ARE-luciferase activity, Nrf2-ARE binding activity, chymotrypsin-like activity, and downstream HO-1 and NQO-1 expression, but decreased cytosolic Kelch-like ECH-associated protein 1 (Keap1) expression. Results also reveal that the ERK/p38-Nrf2 pathway was involved in the activation of HO-1 and NQO-1 expression by apo-8'-lycopenal using Nrf2 siRNA and ERK/p38 specific inhibitors. In addition, the activation time of lycopene on nuclear Nrf2 accumulation was slower than that of apo-8'-lycopenal, suggesting that the chemopreventive effects of lycopene may be partially attributed to apo-8'-lycopenal. Lycopene has been shown to inhibit tumor metastasis both in vitro and in vivo, but little is known whether apo-8'-lycopenal has similar effects. Therefore, we investigated the anti-metastatic effect of apo-8'-lycopenal (1-10 μM) in comparison with lycopene (10 μM) and the possible mechanisms underlying such actions of apo-8'-lycopenal in a highly invasive hepatocarcinoma SK-Hep-1 cell line. We found that both apo-8'-lycopenal and lycopene inhibited the invasion and migration of SK-Hep-1 cells, and the effect of apo-8'-lycopenal was stronger than that of lycopene at the same concentration (10 μM). Mechanistically, apo-8'-lycopenal significantly: (1) decreased the activities and protein expression of matrix metalloproteinase-2 (MMP-2) and -9; (2) increased the protein expression of nm23-H1 and the tissue inhibitor of matrix metalloproteinase (TIMP)-1 and -2; (3) suppressed protein expression of Rho small GTPases; and (4) inhibited focal adhesion kinase (FAK)-mediated signaling pathway, such as ERK/p38 and PI3K-Akt axis. We conclud that apo-8'-lycopenal possesses anti-metastatic activity in SK-Hep-1 cells and that this effect is stronger than that of lycopene, suggesting that the anti-metastatic effect may be attributed, at least in part, to its metabolites such as apo-8'-lycopenal. In addition to these findings, we found that apo-8'-lycopenal significantly decreased levels of vascular endothelial growth factor (VEGF) in SK-Hep-1 cells. VEGF, an endothelium-specific secreted protein, plays an important role in angiogenesis. Therefore, we then went on to study the anti-angiogenic effect of apo-8'-lycopenal by employing an ex vivo assay to substantiate the anti-angiogenic action of apo-8'-lycopenal in comparison with lycopene, and we determined its molecular mechanisms in human umbilical vein endothelial cells (HUVECs). The anti-angiogenic activity of apo-8'-lycopenal was confirmed by ex vivo rat aortic ring assay, and this inhibitory effect of apo-8'-lycopenal was stronger than that of lycopene at the same concentration (10 μM). Mechanistically, apo-8'-lycopenal significantly inhibited tube formation, invasion and migration in HUVECs, and such actions were accompanied by regulation of upstream VEGF receptor 2 (VEGFR2)-mediated activities of MMP-2 and protein expression of TIMP-2. We conclude that apo-8'-lycopenal possesses anti-angiogenic activity both in vitro and ex vivo and that this effect is stronger than that of lycopene, suggesting that the anti-angiogenic effect may be attributed, at least in part, to its metabolites such as apo-8'-lycopenal. In summary, this dissertation research demonstrates that (1) apo-8'-lycopenal possess chemopreventive and chemotherapeutic activity including induction of Nrf2-ARE system, anti-metastasis and anti-angiogenesis; (2) the chemopreventive or chemotherapeutic activity of lycopene may be attributed, at least in part, to its metabolites such as apo-8'-lycopenal. Overall, we conclude that apo-8'-lycopenal has the potential to be used as a chemopreventive or chemotherapeutic agent.
URI: http://hdl.handle.net/11455/51954
其他識別: U0005-1701201216583900
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-1701201216583900
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