癌症的形成是一多重的步驟，牽涉到許多基因與分子層次的改變；發炎反應則在腫瘤促進作用其間扮演重要角色，因此抗發炎被視為癌症化學預防的重要方針。近來柑橘類水果中的類黃酮因具有不同的生物活性而備受矚目。5-hydroxy-3,6,7,8,3’,4’-hexamethoxyflavone（5-OH-HxMF）為PMF化合物中的一種，且大部分只存在於柑橘（citrus）屬的水果，特別是甜橙（sweet orange）的果皮。在我們先前的研究顯示，PMFs中的5-OH-HxMF對腫瘤細胞的生長有明顯的抑制作用，亦可誘導人類血癌細胞的凋亡；然而其抗發炎活性與分子機制則尚未被探討。因此在第一部分的研究中，實驗設計利用小鼠皮膚塗抹12-O-tetradecanoylphorbol-13-acetate（TPA）誘導皮膚發炎反應的模式探討5-OH-HxMF抑制發炎反應的活性與分子機制。實驗結果顯示，局部塗抹5-OH-HxMF （1或3 umol）可有效的抑制TPA所誘發的表皮發炎指標（表皮厚度與白血球浸潤），並降低inductible nitric oxide synthase（iNOS）與cyclooxygenase-2（COX-2）發炎酵素的基因和蛋白質表現。另外在分子機制研究方面亦發現，5-OH-HxMF可抑制TPA引發IkB的磷酸化與降解，因而阻斷了核轉錄因子nuclear factor-kB（NF-kB）轉位（translocation）至細胞核內並喪失了與DNA binding的活性。此外實驗結果亦指出5-OH-HxM亦會抑制TPA引發extracellular signal-regulated kinase 1/2（ERK1/2）、p38 mitogenactivated protein kinase（MAPK）和phosphatidylinositol 3-kinase（PI3K） /Akt的磷酸化以及轉錄因子signal transducer and activator of transcription 3（STAT3）與p65的磷酸化。在皮膚二階段致癌模式的研究中亦發現局部塗抹5-OH-HxMF 可降低7,12-dimethylbenz[a]anthracene（DMBA）/TPA誘發之皮膚腫瘤之數目與大小。綜合以上實驗結果顯示，5-OH-HxMF可能是藉由干擾TPA引起的NF-B和STAT3訊息傳遞而抑制發炎基因的表現，而具有降低皮膚腫瘤形成的能力；這些實驗結果也提供了柑橘果皮中5-OH-HxMF在抗發炎與癌症化學預防上的應用潛力。

5-hydroxy-3,6,7,8,3’,4’-hexamethoxyflavone (5-OH-HxMF), a polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. Herein, we report the first investigation of the inhibitory effects of 5-OH-HxMF on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in mouse skin. We found that the topical application of 5-OH-HxMF can effectively inhibit the transcriptional activation of iNOS and COX-2 mRNA and protein in mouse skin stimulated by TPA. Pre-treatment with 5-OH-HxMF resulted in the reduction of TPA-induced nuclear translocation of nuclear factor-kB (NF-kB) subunit and DNA binding by blocking phosphorylation of inhibitor kB (IkB) a and p65 and subsequent degradation of IkB. In addition, 5-OH-HxMF can inhibit TPA-induced phosphorylation and nuclear translocation of the signal transducer and activator of transcription-3. Moreover, 5-OH-HxMF can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt, which are upstream of NF-kB. We also found that 5-OH-HxMF significantly inhibited TPA-induced mouse skin inflammation by decreasing inflammatory parameters. Furthermore, 5-OH-HxMF significantly inhibited 7, 12- dimethylbenz[a]anthracene/TPA-induced skin tumor formation by reducing the tumor incidence and tumor multiplicity of papillomas at 20 weeks. Therefore, all these results revealed for the first time that 5-OH-HxMF is an effective antitumor agent and its inhibitory effect is through the down-regulation of inflammatory iNOS and COX-2 gene expression in mouse skin, suggesting that 5-OH-HxMF is a novel functional agent capable of preventing inflammation-associated tumorigenesis.

第壹部分
Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K., and Sethi, G. (2006) Inflammation and cancer: how hot is the link? Biochem Pharmacol 72: 1605-1621.
Allavena, P., Garlanda, C., Borrello, M. G., Sica, A., and Mantovani, A. (2008) Pathways connecting inflammation and cancer. Curr Opin Genet Dev 18: 3-10.
Araldi, E. M., Dell'aica, I., Sogno, I., Lorusso, G., Garbisa, S., and Albini, A. (2008) Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer. Curr Cancer Drug Targets 8: 146-155.
Balkwill, F. and Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet 357: 539-545.
Berenblum, I. and Shubik, P. (1949) The persistence of latent tumour cells induced in the mouse's skin by a single application of 9:10-dimethyl-1:2-benzanthracene. Br J Cancer 3: 384-386.
Breinholt, V. M., Rasmussen, S. E., Brosen, K., and Friedberg, T. H. (2003) In vitro metabolism of genistein and tangeretin by human and murine cytochrome P450s. Pharmacol Toxicol 93: 14-22.
Busby, J. E. and Kamat, A. M. (2006) Chemoprevention for bladder cancer. J Urol 176: 1914-1920.
Chan, K. S., Sano, S., Kataoka, K., Abel, E., Carbajal, S., Beltran, L. et al. (2008) Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis. Oncogene 27: 1087-1094.
Chan, K. S., Sano, S., Kiguchi, K., Anders, J., Komazawa, N., Takeda, J. et al. (2004) Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest 114: 720-728.
Chau, C. F., Huang, Y. L., and Lee, M. H. (2003) In vitro hypoglycemic effects of different insoluble fiber-rich fractions prepared from the peel of Citrus sinensis L. cv. Liucheng. J Agric Food Chem 51: 6623-6626.
Chen, K. H., Weng, M. S., and Lin, J. K. (2007) Tangeretin suppresses IL-1beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem Pharmacol 73: 215-227.
Choi, S. Y., Hwang, J. H., Ko, H. C., Park, J. G., and Kim, S. J. (2007) Nobiletin from citrus fruit peel inhibits the DNA-binding activity of NF-kappaB and ROS production in LPS-activated RAW 264.7 cells. J Ethnopharmacol 113: 149-155.
Chun, K. S., Cha, H. H., Shin, J. W., Na, H. K., Park, K. K., Chung, W. Y. et al. (2004a) Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-kappaB. Carcinogenesis 25: 445-454.
Chun, K. S., Keum, Y. S., Han, S. S., Song, Y. S., Kim, S. H., and Surh, Y. J. (2003) Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-kappaB activation. Carcinogenesis 24: 1515-1524.
Chun, K. S., Kim, S. H., Song, Y. S., and Surh, Y. J. (2004b) Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. Carcinogenesis 25: 713-722.
Cianchi, F., Cortesini, C., Fantappie, O., Messerini, L., Sardi, I., Lasagna, N. et al. (2004) Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer. Clin Cancer Res 10: 2694-2704.
Darnell, J. E., Jr., Kerr, I. M., and Stark, G. R. (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415-1421.
de Visser, K. E. and Coussens, L. M. (2006) The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol 13: 118-137.
De, F. S. and Ferguson, L. R. (2005) Overview of mechanisms of cancer chemopreventive agents. Mutat Res 591: 8-15.
DiGiovanni, J. and Juchau, M. R. (1980) Biotransformation and bioactivation of 7, 12-dimethylbenz[a]anthracene (7, 12-DMBA). Drug Metab Rev 11: 61-101.
Fazilatun, N., Nornisah, M., and Zhari, I. (2005) Superoxide radical scavenging properties of extracts and flavonoids isolated from the leaves of Blumea balsamifera. Pharmaceutical Biology 43: 15-20.
Ferguson, L. R., Bronzetti, G., and De, F. S. (2005) Mechanistic approaches to chemoprevention of mutation and cancer. Mutat Res 591: 3-7.
Galdiero, M., Vitiello, M., D'Isanto, M., Raieta, K., and Galdiero, E. (2006) STAT1 and STAT3 phosphorylation by porins are independent of JAKs but are dependent on MAPK pathway and plays a role in U937 cells production of interleukin-6. Cytokine 36: 218-228.
Germano, G., Allavena, P., and Mantovani, A. (2008) Cytokines as a key component of cancer-related inflammation. Cytokine 43: 374-379.
Ghai, G., Rosen, R., Ho, C.-T., Chen, K. Y., Telang, N., Telang, N. et al. Extracts of orange peel for prevention and treatment of cancer. WO Patent[ 01/21137]. 2001.
Ref Type: Patent
Goswami, B., Rajappa, M., Sharma, M., and Sharma, A. (2008) Inflammation: its role and interplay in the development of cancer, with special focus on gynecological malignancies. Int J Gynecol Cancer 18: 591-599.
Guha, M. and Mackman, N. (2001) LPS induction of gene expression in human monocytes. Cell Signal 13: 85-94.
Hanahan, D. and Weinberg, R. A. (2000) The hallmarks of cancer. Cell 100: 57-70.
Ho, S. C. and Lin, C. C. (2008) Investigation of heat treating conditions for enhancing the anti-inflammatory activity of citrus fruit (Citrus reticulata) peels. J Agric Food Chem 56: 7976-7982.
Hwang, D. M., Kundu, J. K., Shin, J. W., Lee, J. C., Lee, H. J., and Surh, Y. J. (2007) cis-9,trans-11-conjugated linoleic acid down-regulates phorbol ester-induced NF-kappaB activation and subsequent COX-2 expression in hairless mouse skin by targeting IkappaB kinase and PI3K-Akt. Carcinogenesis 28: 363-371.
Kandaswami, C., Perkins, E., Soloniuk, D. S., Drzewiecki, G., and Middleton E Jr (1991) Antiproliferative effects of citrus flavonoids on a human squamous cell carcinoma in vitro. Cancer Lett 56: 147-152.
Klein, G., Vellenga, E., Fraaije, M. W., Kamps, W. A., and de Bont, E. S. (2004) The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia. Crit Rev Oncol Hematol 50: 87-100.
Kundu, J. K. and Surh, Y. J. (2008) Inflammation: gearing the journey to cancer. Mutat Res 659: 15-30.
Kupferman, M. E., Fini, M. E., Muller, W. J., Weber, R., Cheng, Y., and Muschel, R. J. (2000) Matrix metalloproteinase 9 promoter activity is induced coincident with invasion during tumor progression. Am J Pathol 157: 1777-1783.
Lee, A. K., Sung, S. H., Kim, Y. C., and Kim, S. G. (2003) Inhibition of lipopolysaccharide-inducible nitric oxide synthase, TNF-alpha and COX-2 expression by sauchinone effects on I-kappaBalpha phosphorylation, C/EBP and AP-1 activation. Br J Pharmacol 139: 11-20.
Lee, J. C., Kundu, J. K., Hwang, D. M., Na, H. K., and Surh, Y. J. (2007) Humulone inhibits phorbol ester-induced COX-2 expression in mouse skin by blocking activation of NF-kappaB and AP-1: IkappaB kinase and c-Jun-N-terminal kinase as respective potential upstream targets. Carcinogenesis 28: 1491-1498.
Li, S., Lo, C. Y., and Ho, C. T. (2006) Hydroxylated polymethoxyflavones and methylated flavonoids in sweet orange (Citrus sinensis) peel. J Agric Food Chem 54: 4176-4185.
Li, S., Pan, M. H., Lai, C. S., Lo, C. Y., Dushenkov, S., and Ho, C. T. (2007) Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines. Bioorg Med Chem 15: 3381-3389.
Lichius, J. J., Thoison, O., Montagnac, A., Pais, M., Gueritte-Voegelein, F., Sevenet, T. et al. (1994) Antimitotic and cytotoxic flavonols from Zieridium pseudobtusifolium and Acronychia porteri. J Nat Prod 57: 1012-1016.
Lin, N., Sato, T., Takayama, Y., Mimaki, Y., Sashida, Y., Yano, M. et al. (2003) Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem Pharmacol 65: 2065-2071.
Lomnitski, L., Bergman, M., Nyska, A., Ben-Shaul, V., and Grossman, S. (2003) Composition, efficacy, and safety of spinach extracts. Nutr Cancer 46: 222-231.
Lu, H., Ouyang, W., and Huang, C. (2006) Inflammation, a key event in cancer development. Mol Cancer Res 4: 221-233.
Luo, G., Guan, X., and Zhou, L. (2008) Apoptotic effect of citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer Biol Ther 7: 966-973.
Madrid, L. V., Mayo, M. W., Reuther, J. Y., and Baldwin, A. S., Jr. (2001) Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 276: 18934-18940.
Maeda, S. and Omata, M. (2008) Inflammation and cancer: role of nuclear factor-kappaB activation. Cancer Sci 99: 836-842.
Mandriota, S. J. and Pepper, M. S. (1997) Vascular endothelial growth factor-induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor. J Cell Sci 110 ( Pt 18): 2293-2302.
Manthey, J. A. and Manthey, C. L. Montanari Inhibition of cytokine production by polymethoxylated flavones. United States Patent[ 6184246]. 2001.
Ref Type: Patent
Mantovani, A., Allavena, P., Sica, A., and Balkwill, F. (2008) Cancer-related inflammation. Nature 454: 436-444.
Marrero, M. B., Venema, V. J., He, H., Caldwell, R. B., and Venema, R. C. (1998) Inhibition by the JAK/STAT pathway of IFNgamma- and LPS-stimulated nitric oxide synthase induction in vascular smooth muscle cells. Biochem Biophys Res Commun 252: 508-512.
Middleton E Jr, Kandaswami, C., and Theoharides, T. C. (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52: 673-751.
Morley, K. L., Ferguson, P. J., and Koropatnick, J. (2007) Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Lett 251: 168-178.
Mueller, M. M. (2006) Inflammation in epithelial skin tumours: old stories and new ideas. Eur J Cancer 42: 735-744.
Murakami, A., Nakamura, Y., Torikai, K., Tanaka, T., Koshiba, T., Koshimizu, K. et al. (2000) Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res 60: 5059-5066.
Murakami, A. and Ohigashi, H. (2004) Division of food science and biotechnology. pp. 187-211.
Neugut, A. I., Lebwohl, B., and Hershman, D. L. (2007) Cancer chemoprevention: how do we know what works? J Clin Oncol 25: 1461-1462.
Pan, M. H., Chen, W. J., Lin-Shiau, S. Y., Ho, C. T., and Lin, J. K. (2002) Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis 23: 1677-1684.
Pan, M. H. and Ho, C. T. (2008) Chemopreventive effects of natural dietary compounds on cancer development. Chem Soc Rev 37: 2558-2574.
Pan, M. H., Lai, Y. S., Lai, C. S., Wang, Y. J., Li, S., Lo, C. Y. et al. (2007) 5-Hydroxy-3,6,7,8,3',4'-hexamethoxyflavone induces apoptosis through reactive oxygen species production, growth arrest and DNA damage-inducible gene 153 expression, and caspase activation in human leukemia cells. J Agric Food Chem 55: 5081-5091.
Pedranzini, L., Leitch, A., and Bromberg, J. (2004) Stat3 is required for the development of skin cancer. J Clin Invest 114: 619-622.
Qiu, P., Dong, P., Guan, H., Li, S., Ho, C. T., Pan, M. H. et al. (2010) Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Mol Nutr Food Res.
Raick, A. N. (1973b) Late ultrastructural changes induced by 12-O-tetradecanoyl-phorbol-13-acetate in mouse epidermis and their reversal. Cancer Res 33: 1096-1103.
Raick, A. N. (1973a) Ultrastructural, histological, and biochemical alterations produced by 12-O-tetradecanoyl-phorbol-13-acetate on mouse epidermis and their relevance to skin tumor promotion. Cancer Res 33: 269-286.
Raick, A. N. and Burdzy, K. (1973) Ultrastructural and biochemical changes induced in mouse epidermis by a hyperplastic agent, ethylphenylpropiolate. Cancer Res 33: 2221-2230.
Ramos, S. (2008) Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol Nutr Food Res 52: 507-526.
Reiners, J. J., Jr., Kodari, E., Cappel, R. E., and Gilbert, H. F. (1991a) Assessment of the antioxidant/prooxidant status of murine skin following topical treatment with 12-O-tetradecanoylphorbol-13-acetate and throughout the ontogeny of skin cancer. Part II: Quantitation of glutathione and glutathione disulfide. Carcinogenesis 12: 2345-2352.
Reiners, J. J., Jr., Thai, G., Rupp, T., and Cantu, A. R. (1991b) Assessment of the antioxidant/prooxidant status of murine skin following topical treatment with 12-O-tetradecanoylphorbol-13-acetate and throughout the ontogeny of skin cancer. Part I: Quantitation of superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase. Carcinogenesis 12: 2337-2343.
Sakurai, H., Suzuki, S., Kawasaki, N., Nakano, H., Okazaki, T., Chino, A. et al. (2003) Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway. J Biol Chem 278: 36916-36923.
Sato, T., Koike, L., Miyata, Y., Hirata, M., Mimaki, Y., Sashida, Y. et al. (2002) Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res 62: 1025-1029.
Schindler, C. W. (2002) Series introduction. JAK-STAT signaling in human disease. J Clin Invest 109: 1133-1137.
Sergeev, I. N., Ho, C. T., Li, S., Colby, J., and Dushenkov, S. (2007) Apoptosis-inducing activity of hydroxylated polymethoxyflavones and polymethoxyflavones from orange peel in human breast cancer cells. Mol Nutr Food Res 51: 1478-1484.
Sergeev, I. N., Li, S., Colby, J., Ho, C. T., and Dushenkov, S. (2006) Polymethoxylated flavones induce Ca(2+)-mediated apoptosis in breast cancer cells. Life Sci 80: 245-253.
Sergeev, I. N., Li, S., Ho, C. T., Rawson, N. E., and Dushenkov, S. (2009) Polymethoxyflavones activate Ca2+-dependent apoptotic targets in adipocytes. J Agric Food Chem 57: 5771-5776.
Shiming Li, Min-Hsiung Pan, Chih-Yu Lo, Di Tan, Yu Wang, Fereidoon Shahidi et al. (2009) Chemistry and health effects of polymethoxyflavones and hydroxylated polymethoxyflavones. Journal of Functional Foods 1: 2-12.
Singh, R. P. and Agarwal, R. (2007) Inducible nitric oxide synthase-vascular endothelial growth factor axis: a potential target to inhibit tumor angiogenesis by dietary agents. Curr Cancer Drug Targets 7: 475-483.
Slaga, T. J., DiGiovanni, J., Winberg, L. D., and Budunova, I. V. (1995) Skin carcinogenesis: characteristics, mechanisms, and prevention. Prog Clin Biol Res 391: 1-20.
Sporn, M. B., Dunlop, N. M., Newton, D. L., and Smith, J. M. (1976) Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 35: 1332-1338.
Surh, Y. J. (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3: 768-780.
Suzuki, H., Chiba, T., Kobayashi, M., Takeuchi, M., Furuichi, K., and Tanaka, K. (1999) In vivo and in vitro recruitment of an IkappaBalpha-ubiquitin ligase to IkappaBalpha phosphorylated by IKK, leading to ubiquitination. Biochem Biophys Res Commun 256: 121-126.
Tang, M., Ogawa, K., Asamoto, M., Hokaiwado, N., Seeni, A., Suzuki, S. et al. (2007) Protective effects of citrus nobiletin and auraptene in transgenic rats developing adenocarcinoma of the prostate (TRAP) and human prostate carcinoma cells. Cancer Sci 98: 471-477.
Tsai, H. L., Chang, S. K., and Chang, S. J. (2007) Antioxidant content and free radical scavenging ability of fresh red pummelo [Citrus grandis (L.) Osbeck] juice and freeze-dried products. J Agric Food Chem 55: 2867-2872.
Whiteside, T. L. (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27: 5904-5912.
Whitman, S. C., Kurowska, E. M., Manthey, J. A., and Daugherty, A. (2005) Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis 178: 25-32.
Xiao, H., Yang, C. S., Li, S., Jin, H., Ho, C. T., and Patel, T. (2009) Monodemethylated polymethoxyflavones from sweet orange (Citrus sinensis) peel inhibit growth of human lung cancer cells by apoptosis. Mol Nutr Food Res 53: 398-406.
Yokogami, K., Wakisaka, S., Avruch, J., and Reeves, S. A. (2000) Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 10: 47-50.
Yoshimizu, N., Otani, Y., Saikawa, Y., Kubota, T., Yoshida, M., Furukawa, T. et al. (2004) Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment Pharmacol Ther 20 Suppl 1: 95-101.
Yu, H., Kortylewski, M., and Pardoll, D. (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7: 41-51

第貳部分
Al, R. M., Nakajima, A., Saigusa, D., Tetsu, N., Maruyama, Y., Shibuya, M. et al. (2009) 4'-Demethylnobiletin, a bioactive metabolite of nobiletin enhancing PKA/ERK/CREB signaling, rescues learning impairment associated with NMDA receptor antagonism via stimulation of the ERK cascade. Biochemistry 48: 7713-7721.
Astrup, E. G. and Paulsen, J. E. (1981) Changes in epidermal polyamine biosynthesis and specific activity of DNA following a single application of 12-O-tetradecanoyl-phorbol-13-acetate to hairless mouse skin. Carcinogenesis 2: 545-551.
Breinholt, V. M., Rasmussen, S. E., Brosen, K., and Friedberg, T. H. (2003) In vitro metabolism of genistein and tangeretin by human and murine cytochrome P450s. Pharmacol Toxicol 93: 14-22.
Chan, K. S., Sano, S., Kiguchi, K., Anders, J., Komazawa, N., Takeda, J. et al. (2004) Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest 114: 720-728.
Choi, S. Y., Hwang, J. H., Ko, H. C., Park, J. G., and Kim, S. J. (2007) Nobiletin from citrus fruit peel inhibits the DNA-binding activity of NF-kappaB and ROS production in LPS-activated RAW 264.7 cells. J Ethnopharmacol 113: 149-155.
Chun, K. S., Cha, H. H., Shin, J. W., Na, H. K., Park, K. K., Chung, W. Y. et al. (2004a) Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-kappaB. Carcinogenesis 25: 445-454.
Chun, K. S., Kim, S. H., Song, Y. S., and Surh, Y. J. (2004b) Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. Carcinogenesis 25: 713-722.
Denning, M. F. (2004) Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms. Int J Biochem Cell Biol 36: 1141-1146.
Dietrich, D. R. (1993) Toxicological and pathological applications of proliferating cell nuclear antigen (PCNA), a novel endogenous marker for cell proliferation. Crit Rev Toxicol 23: 77-109.
Eguchi, A., Murakami, A., Li, S., Ho, C. T., and Ohigashi, H. (2007) Suppressive effects of demethylated metabolites of nobiletin on phorbol ester-induced expression of scavenger receptor genes in THP-1 human monocytic cells. Biofactors 31: 107-116.
Ito, A., Ishiwa, J., Sato, T., Mimaki, Y., and Sashida, Y. (1999) The citrus flavonoid nobiletin suppresses the production and gene expression of matrix metalloproteinases-9/gelatinase B in rabbit synovial cells. Ann N Y Acad Sci 878: 632-634.
Iuvone, T., D'Acquisto, F., Van, O. N., Di, R. M., Carnuccio, R., and Herman, A. G. (1998) Evidence that inducible nitric oxide synthase is involved in LPS-induced plasma leakage in rat skin through the activation of nuclear factor-kappaB. Br J Pharmacol 123: 1325-1330.
Jana, S. and Mandlekar, S. (2009) Role of phase II drug metabolizing enzymes in cancer chemoprevention. Curr Drug Metab 10: 595-616.
Kansy, M., Senner, F., and Gubernator, K. (1998) Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem 41: 1007-1010.
Kazanietz, M. G. (2005) Targeting protein kinase C and "non-kinase" phorbol ester receptors: emerging concepts and therapeutic implications. Biochim Biophys Acta 1754: 296-304.
Kikkawa, U., Takai, Y., Tanaka, Y., Miyake, R., and Nishizuka, Y. (1983) Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters. J Biol Chem 258: 11442-11445.
Kunimasa, K., Kuranuki, S., Matsuura, N., Iwasaki, N., Ikeda, M., Ito, A. et al. (2009) Identification of nobiletin, a polymethoxyflavonoid, as an enhancer of adiponectin secretion. Bioorg Med Chem Lett 19: 2062-2064.
Kurowska, E. M. and Manthey, J. A. (2004) Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia. J Agric Food Chem 52: 2879-2886.
Lee, A. K., Sung, S. H., Kim, Y. C., and Kim, S. G. (2003) Inhibition of lipopolysaccharide-inducible nitric oxide synthase, TNF-alpha and COX-2 expression by sauchinone effects on I-kappaBalpha phosphorylation, C/EBP and AP-1 activation. Br J Pharmacol 139: 11-20.
Lee, Y. S., Cha, B. Y., Saito, K., Yamakawa, H., Choi, S. S., Yamaguchi, K. et al. (2010) Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochem Pharmacol 79: 1674-1683.
Li, S., Pan, M. H., Lai, C. S., Lo, C. Y., Dushenkov, S., and Ho, C. T. (2007a) Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines. Bioorg Med Chem 15: 3381-3389.
Li, S., Sang, S., Pan, M. H., Lai, C. S., Lo, C. Y., Yang, C. S. et al. (2007b) Anti-inflammatory property of the urinary metabolites of nobiletin in mouse. Bioorg Med Chem Lett 17: 5177-5181.
Li, S., Wang, Z., Sang, S., Huang, M. T., and Ho, C. T. (2006) Identification of nobiletin metabolites in mouse urine. Mol Nutr Food Res 50: 291-299.
Lin, N., Sato, T., Takayama, Y., Mimaki, Y., Sashida, Y., Yano, M. et al. (2003) Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem Pharmacol 65: 2065-2071.
Lo, Y. H., Pan, M. H., Li, S., Yen, J. H., Kou, M. C., Ho, C. T. et al. (2010) Nobiletin metabolite, 3',4'-dihydroxy-5,6,7,8-tetramethoxyflavone, inhibits LDL oxidation and down-regulates scavenger receptor expression and activity in THP-1 cells. Biochim Biophys Acta 1801: 114-126.
Luo, G., Guan, X., and Zhou, L. (2008) Apoptotic effect of citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer Biol Ther 7: 966-973.
Luo, J. H., Xing, W. Q., and Weinstein, I. B. (1995) The phorbol ester TPA markedly enhances the binding of calcium to the regulatory domain of protein kinase C beta 1 in the presence of phosphatidylserine. Carcinogenesis 16: 897-905.
Manach, C. and Donovan, J. L. (2004) Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic Res 38: 771-785.
Manach, C., Scalbert, A., Morand, C., Remesy, C., and Jimenez, L. (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79: 727-747.
Matsuzaki, K., Yamakuni, T., Hashimoto, M., Haque, A. M., Shido, O., Mimaki, Y. et al. (2006) Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats. Neurosci Lett 400: 230-234.
Mills, K. J., Bocckino, S. B., Burns, D. J., Loomis, C. R., and Smart, R. C. (1992) Alterations in protein kinase C isozymes alpha and beta 2 in activated Ha-ras containing papillomas in the absence of an increase in diacylglycerol. Carcinogenesis 13: 1113-1120.
Minagawa, A., Otani, Y., Kubota, T., Wada, N., Furukawa, T., Kumai, K. et al. (2001) The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice. Jpn J Cancer Res 92: 1322-1328.
Miyata, Y., Sato, T., Imada, K., Dobashi, A., Yano, M., and Ito, A. (2008) A citrus polymethoxyflavonoid, nobiletin, is a novel MEK inhibitor that exhibits antitumor metastasis in human fibrosarcoma HT-1080 cells. Biochem Biophys Res Commun 366: 168-173.
Morley, K. L., Ferguson, P. J., and Koropatnick, J. (2007) Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Lett 251: 168-178.
Munoz, Y., Garrido, A., and Valladares, L. (2009) Equol is more active than soy isoflavone itself to compete for binding to thromboxane A(2) receptor in human platelets. Thromb Res 123: 740-744.
Murakami, A., Koshimizu, K., Ohigashi, H., Kuwahara, S., Kuki, W., Takahashi, Y. et al. (2002) Characteristic rat tissue accumulation of nobiletin, a chemopreventive polymethoxyflavonoid, in comparison with luteolin. Biofactors 16: 73-82.
Murakami, A., Kuwahara, S., Takahashi, Y., Ito, C., Furukawa, H., Ju-Ichi, M. et al. (2001) In vitro absorption and metabolism of nobiletin, a chemopreventive polymethoxyflavonoid in citrus fruits. Biosci Biotechnol Biochem 65: 194-197.
Murakami, A., Nakamura, Y., Torikai, K., Tanaka, T., Koshiba, T., Koshimizu, K. et al. (2000) Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res 60: 5059-5066.
Murakami, A., Shigemori, T., and Ohigashi, H. (2005) Zingiberaceous and citrus constituents, 1'-acetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 murine macrophages through different modes of action. J Nutr 135: 2987S-2992S.
Nagase, H., Omae, N., Omori, A., Nakagawasai, O., Tadano, T., Yokosuka, A. et al. (2005a) Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities. Biochem Biophys Res Commun 337: 1330-1336.
Nagase, H., Yamakuni, T., Matsuzaki, K., Maruyama, Y., Kasahara, J., Hinohara, Y. et al. (2005b) Mechanism of neurotrophic action of nobiletin in PC12D cells. Biochemistry 44: 13683-13691.
Nielsen, S. E., Breinholt, V., Cornett, C., and Dragsted, L. O. (2000) Biotransformation of the citrus flavone tangeretin in rats. Identification of metabolites with intact flavane nucleus. Food Chem Toxicol 38: 739-746.
Nielsen, S. E., Breinholt, V., Justesen, U., Cornett, C., and Dragsted, L. O. (1998) In vitro biotransformation of flavonoids by rat liver microsomes. Xenobiotica 28: 389-401.
Okada, K., Wangpoengtrakul, C., Tanaka, T., Toyokuni, S., Uchida, K., and Osawa, T. (2001) Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. J Nutr 131: 2090-2095.
Prasain, J. K. and Barnes, S. (2007) Metabolism and bioavailability of flavonoids in chemoprevention: current analytical strategies and future prospectus. Mol Pharm 4: 846-864.
Rimbach, G., De Pascual-Teresa, S., Ewins, B. A., Matsugo, S., Uchida, Y., Minihane, A. M. et al. (2003) Antioxidant and free radical scavenging activity of isoflavone metabolites. Xenobiotica 33: 913-925.
Rooprai, H. K., Kandanearatchi, A., Maidment, S. L., Christidou, M., Trillo-Pazos, G., Dexter, D. T. et al. (2001) Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro. Neuropathol Appl Neurobiol 27: 29-39.
Saito, T., Abe, D., and Sekiya, K. (2007) Nobiletin enhances differentiation and lipolysis of 3T3-L1 adipocytes. Biochem Biophys Res Commun 357: 371-376.
Shiming Li, Min-Hsiung Pan, Chih-Yu Lo, Di Tan, Yu Wang, Fereidoon Shahidi et al. (2009) Chemistry and health effects of polymethoxyflavones and hydroxylated polymethoxyflavones. Journal of Functional Foods 1: 2-12.
Sun, S. Y., Hail, N., Jr., and Lotan, R. (2004) Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst 96: 662-672.
Suzuki, M., Nakamura, T., Iyoki, S., Fujiwara, A., Watanabe, Y., Mohri, K. et al. (2005a) Elucidation of anti-allergic activities of curcumin-related compounds with a special reference to their anti-oxidative activities. Biol Pharm Bull 28: 1438-1443.
Suzuki, M., Sasaki, K., Yoshizaki, F., Oguchi, K., Fujisawa, M., and Cyong, J. C. (2005b) Anti-hepatitis C virus effect of citrus unshiu peel and its active ingredient nobiletin. Am J Chin Med 33: 87-94.
Tamvakopoulos, C., Dimas, K., Sofianos, Z. D., Hatziantoniou, S., Han, Z., Liu, Z. L. et al. (2007) Metabolism and anticancer activity of the curcumin analogue, dimethoxycurcumin. Clin Cancer Res 13: 1269-1277.
Tanaka, S., Sato, T., Akimoto, N., Yano, M., and Ito, A. (2004) Prevention of UVB-induced photoinflammation and photoaging by a polymethoxy flavonoid, nobiletin, in human keratinocytes in vivo and in vitro. Biochem Pharmacol 68: 433-439.
Van de Waterbeemd, H., Lennernas, H., and Artursson, P. (2003) Methods in principal medicinal chemistry. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA.
van Iersel, M. L., Verhagen, H., and van Bladeren, P. J. (1999) The role of biotransformation in dietary (anti)carcinogenesis. Mutat Res 443: 259-270.
Walle, T. (2007) Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass? Semin Cancer Biol 17: 354-362.
Wang, H. Q. and Smart, R. C. (1999b) Overexpression of protein kinase C-alpha in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-alpha expression but not tumor promotion. J Cell Sci 112 ( Pt 20): 3497-3506.
Wang, H. Q. and Smart, R. C. (1999a) Overexpression of protein kinase C-alpha in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-alpha expression but not tumor promotion. J Cell Sci 112 ( Pt 20): 3497-3506.
Yan, Z. and Caldwell, G. W. (2001) Metabolism profiling, and cytochrome P450 inhibition & induction in drug discovery. Curr Top Med Chem 1: 403-425.
Yasuda, T., Yoshimura, Y., Yabuki, H., Nakazawa, T., Ohsawa, K., Mimaki, Y. et al. (2003) Urinary metabolites of nobiletin orally administered to rats. Chem Pharm Bull (Tokyo) 51: 1426-1428.
Yoshimizu, N., Otani, Y., Saikawa, Y., Kubota, T., Yoshida, M., Furukawa, T. et al. (2004) Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment Pharmacol Ther 20 Suppl 1: 95-101.
Yu, H., Kortylewski, M., and Pardoll, D. (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7: 41-51.

第參部分
Ahmed, F. E. (2005) Molecular markers that predict response to colon cancer therapy. Expert Rev Mol Diagn 5: 353-375.
Ahn, B. and Ohshima, H. (2001) Suppression of intestinal polyposis in Apc(Min/+) mice by inhibiting nitric oxide production. Cancer Res 61: 8357-8360.
Amado, R. G., Wolf, M., Peeters, M., Van, C. E., Siena, S., Freeman, D. J. et al. (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26: 1626-1634.
Aranganathan, S., Selvam, J. P., and Nalini, N. (2008) Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: a dose-dependent study. J Pharm Pharmacol 60: 1385-1392.
Ballinger, A. B. and Anggiansah, C. (2007) Colorectal cancer. BMJ 335: 715-718.
Benson, A. B., III (2007) Epidemiology, disease progression, and economic burden of colorectal cancer. J Manag Care Pharm 13: S5-18.
Bird, R. P. (1987) Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 37: 147-151.
Bird, R. P. (1995) Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Lett 93: 55-71.
Biscardi, J. S., Maa, M. C., Tice, D. A., Cox, M. E., Leu, T. H., and Parsons, S. J. (1999) c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem 274: 8335-8343.
Bissahoyo, A., Pearsall, R. S., Hanlon, K., Amann, V., Hicks, D., Godfrey, V. L. et al. (2005) Azoxymethane is a genetic background-dependent colorectal tumor initiator and promoter in mice: effects of dose, route, and diet. Toxicol Sci 88: 340-345.
Cardone, M. H., Roy, N., Stennicke, H. R., Salvesen, G. S., Franke, T. F., Stanbridge, E. et al. (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282: 1318-1321.
Cheng, L. and Lai, M. D. (2003) Aberrant crypt foci as microscopic precursors of colorectal cancer. World J Gastroenterol 9: 2642-2649.
Chung, F. L., Conaway, C. C., Rao, C. V., and Reddy, B. S. (2000) Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 21: 2287-2291.
Cohen, G., Mustafi, R., Chumsangsri, A., Little, N., Nathanson, J., Cerda, S. et al. (2006) Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci. Cancer Res 66: 5656-5664.
Conacci-Sorrell, M., Zhurinsky, J., and Ben-Ze'ev, A. (2002) The cadherin-catenin adhesion system in signaling and cancer. J Clin Invest 109: 987-991.
Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M., and Hemmings, B. A. (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785-789.
Dorudi, S., Sheffield, J. P., Poulsom, R., Northover, J. M., and Hart, I. R. (1993) E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. Am J Pathol 142: 981-986.
DuBois, R. N., Radhika, A., Reddy, B. S., and Entingh, A. J. (1996) Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors. Gastroenterology 110: 1259-1262.
Eberhart, C. E., Coffey, R. J., Radhika, A., Giardiello, F. M., Ferrenbach, S., and DuBois, R. N. (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107: 1183-1188.
Emlet, D. R., Moscatello, D. K., Ludlow, L. B., and Wong, A. J. (1997) Subsets of epidermal growth factor receptors during activation and endocytosis. J Biol Chem 272: 4079-4086.
Fan, K., Kurihara, N., Abe, S., Ho, C. T., Ghai, G., and Yang, K. (2007) Chemopreventive effects of orange peel extract (OPE). I: OPE inhibits intestinal tumor growth in ApcMin/+ mice. J Med Food 10: 11-17.
Fearon, E. R. and Vogelstein, B. (1990) A genetic model for colorectal tumorigenesis. Cell 61: 759-767.
Fiala, E. S. (1977) Investigations into the metabolism and mode of action of the colon carcinogens 1,2-dimethylhydrazine and azoxymethane. Cancer 40: 2436-2445.
Fiala, E. S., Kulakis, C., Christiansen, G., and Weisburger, J. H. (1978) Inhibition of the metabolism of the colon carcinogen, azoxymethane, by pyrazole. Cancer Res 38: 4515-4521.
Fichera, A., Little, N., Jagadeeswaran, S., Dougherty, U., Sehdev, A., Mustafi, R. et al. (2007) Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis. Cancer Res 67: 827-835.
Frydoonfar, H. R., McGrath, D. R., and Spigelman, A. D. (2003) The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid Naringenin. Colorectal Dis 5: 149-152.
Hayashi, K., Suzuki, R., Miyamoto, S., Shin-Ichiroh, Y., Kohno, H., Sugie, S. et al. (2007) Citrus auraptene suppresses azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db mice. Nutr Cancer 58: 75-84.
Hegde, M. R. and Roa, B. B. (2006) Detecting mutations in the APC gene in familial adenomatous polyposis (FAP). Curr Protoc Hum Genet Chapter 10: Unit.
Hong, M. Y., Chapkin, R. S., Wild, C. P., Morris, J. S., Wang, N., Carroll, R. J. et al. (1999) Relationship between DNA adduct levels, repair enzyme, and apoptosis as a function of DNA methylation by azoxymethane. Cell Growth Differ 10: 749-758.
Itzkowitz, S. H. and Yio, X. (2004) Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 287: G7-17.
Jayaprakasha, G. K., Mandadi, K. K., Poulose, S. M., Jadegoud, Y., Nagana Gowda, G. A., and Patil, B. S. (2008) Novel triterpenoid from Citrus aurantium L. possesses chemopreventive properties against human colon cancer cells. Bioorg Med Chem 16: 5939-5951.
Karapetis, C. S., Khambata-Ford, S., Jonker, D. J., O'Callaghan, C. J., Tu, D., Tebbutt, N. C. et al. (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359: 1757-1765.
Kim, J. M., Araki, S., Kim, D. J., Park, C. B., Takasuka, N., Baba-Toriyama, H. et al. (1998) Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Carcinogenesis 19: 81-85.
Kohno, H., Yoshitani, S., Tsukio, Y., Murakami, A., Koshimizu, K., Yano, M. et al. (2001) Dietary administration of citrus nobiletin inhibits azoxymethane-induced colonic aberrant crypt foci in rats. Life Sci 69: 901-913.
Korinek, V., Barker, N., Morin, P. J., van, W. D., de, W. R., Kinzler, K. W. et al. (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 275: 1784-1787.
Kune, G. and Watson, L. (2006) Colorectal cancer protective effects and the dietary micronutrients folate, methionine, vitamins B6, B12, C, E, selenium, and lycopene. Nutr Cancer 56: 11-21.
LaMont, J. T. and O'Gorman, T. A. Experimental colon cancer. Gastroenterology 75, 1157-1169. 1978.
Ref Type: Journal (Full)
Li, S., Wang, Y., Wang, Z., Xiao, H., Lo, C. Y., Rawson, N. et al. (2009) Quantitative analysis of hydroxylated polymethoxyflavones by high-performance liquid chromatography. Biomed Chromatogr.
Luo, J., Chen, J., Deng, Z. L., Luo, X., Song, W. X., Sharff, K. A. et al. (2007) Wnt signaling and human diseases: what are the therapeutic implications? Lab Invest 87: 97-103.
Malecka-Panas, E., Fligiel, S. E., Relan, N. K., Dutta, S., and Majumdar, A. P. (1996) Azoxymethane enhances ligand-induced activation of EGF receptor tyrosine kinase in the colonic mucosa of rats. Carcinogenesis 17: 233-237.
Mann, J. R. and DuBois, R. N. (2004) Cyclooxygenase-2 and gastrointestinal cancer. Cancer J 10: 145-152.
McLellan, E. A., Medline, A., and Bird, R. P. (1991) Sequential analyses of the growth and morphological characteristics of aberrant crypt foci: putative preneoplastic lesions. Cancer Res 51: 5270-5274.
Michels, K. B., Giovannucci, E., Chan, A. T., Singhania, R., Fuchs, C. S., and Willett, W. C. (2006) Fruit and vegetable consumption and colorectal adenomas in the Nurses' Health Study. Cancer Res 66: 3942-3953.
Miyagi, Y., Om, A. S., Chee, K. M., and Bennink, M. R. (2000) Inhibition of azoxymethane-induced colon cancer by orange juice. Nutr Cancer 36: 224-229.
Miyamoto, S., Yasui, Y., Tanaka, T., Ohigashi, H., and Murakami, A. (2008) Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice. Carcinogenesis 29: 1057-1063.
Moon, R. T., Kohn, A. D., De Ferrari, G. V., and Kaykas, A. (2004) WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5: 691-701.
Morin, P. J., Sparks, A. B., Korinek, V., Barker, N., Clevers, H., Vogelstein, B. et al. (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275: 1787-1790.
Morley, K. L., Ferguson, P. J., and Koropatnick, J. (2007) Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Lett 251: 168-178.
Normanno, N., De, L. A., Bianco, C., Strizzi, L., Mancino, M., Maiello, M. R. et al. (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366: 2-16.
Pan, Q., Hamilton, S. R., Hyland, J., and Boitnott, J. K. (1985) Effects of carcinogen dosage on experimental colonic carcinogenesis by azoxymethane: an ultrastructural study of grossly normal colonic mucosa. J Natl Cancer Inst 74: 689-698.
Phelps, R. A., Broadbent, T. J., Stafforini, D. M., and Jones, D. A. (2009) New perspectives on APC control of cell fate and proliferation in colorectal cancer. Cell Cycle 8: 2549-2556.
Pinto, D. and Clevers, H. (2005) Wnt, stem cells and cancer in the intestine. Biol Cell 97: 185-196.
Qiu, P., Dong, P., Guan, H., Li, S., Ho, C. T., Pan, M. H. et al. (2010) Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Mol Nutr Food Res.
Raju, J., Bielecki, A., Caldwell, D., Lok, E., Taylor, M., Kapal, K. et al. (2009) Soy isoflavones modulate azoxymethane-induced rat colon carcinogenesis exposed pre- and postnatally and inhibit growth of DLD-1 human colon adenocarcinoma cells by increasing the expression of estrogen receptor-beta. J Nutr 139: 474-481.
Rao, C. V., Indranie, C., Simi, B., Manning, P. T., Connor, J. R., and Reddy, B. S. (2002) Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxygenase-2 inhibitor. Cancer Res 62: 165-170.
Rao, C. V., Kawamori, T., Hamid, R., and Reddy, B. S. (1999) Chemoprevention of colonic aberrant crypt foci by an inducible nitric oxide synthase-selective inhibitor. Carcinogenesis 20: 641-644.
Rojas, M., Yao, S., and Lin, Y. Z. (1996) Controlling epidermal growth factor (EGF)-stimulated Ras activation in intact cells by a cell-permeable peptide mimicking phosphorylated EGF receptor. J Biol Chem 271: 27456-27461.
Sano, H., Kawahito, Y., Wilder, R. L., Hashiramoto, A., Mukai, S., Asai, K. et al. (1995) Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55: 3785-3789.
Schmelz, E. M., Xu, H., Sengupta, R., Du, J., Banerjee, S., Sarkar, F. H. et al. (2007) Regression of early and intermediate stages of colon cancer by targeting multiple members of the EGFR family with EGFR-related protein. Cancer Res 67: 5389-5396.
Schneikert, J. and Behrens, J. (2007b) The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut 56: 417-425.
Schneikert, J. and Behrens, J. (2007a) The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut 56: 417-425.
Segditsas, S. and Tomlinson, I. (2006) Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25: 7531-7537.
Silalahi, J. (2002) Anticancer and health protective properties of citrus fruit components. Asia Pac J Clin Nutr 11: 79-84.
Smith, M. L., Hawcroft, G., and Hull, M. A. (2000) The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J Cancer 36: 664-674.
Suzuki, R., Kohno, H., Murakami, A., Koshimizu, K., Ohigashi, H., Yano, M. et al. (2004) Citrus nobiletin inhibits azoxymethane-induced large bowel carcinogenesis in rats. Biofactors 22: 111-114.
Suzuki, R., Kohno, H., Yasui, Y., Hata, K., Sugie, S., Miyamoto, S. et al. (2007) Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice. Int J Cancer 120: 252-258.
Takahashi, M. and Wakabayashi, K. (2004) Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents. Cancer Sci 95: 475-480.
Takayama, T., Katsuki, S., Takahashi, Y., Ohi, M., Nojiri, S., Sakamaki, S. et al. (1998) Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med 339: 1277-1284.
Tanaka, T., Kawabata, K., Kakumoto, M., Makita, H., Hara, A., Mori, H. et al. (1997) Citrus auraptene inhibits chemically induced colonic aberrant crypt foci in male F344 rats. Carcinogenesis 18: 2155-2161.
Tanaka, T., Kohno, H., Tsukio, Y., Honjo, S., Tanino, M., Miyake, M. et al. (2000) Citrus limonoids obacunone and limonin inhibit azoxymethane-induced colon carcinogenesis in rats. Biofactors 13: 213-218.
Tanaka, T., Yasui, Y., Ishigamori-Suzuki, R., and Oyama, T. (2008) Citrus compounds inhibit inflammation- and obesity-related colon carcinogenesis in mice. Nutr Cancer 60 Suppl 1: 70-80.
Tessitore, L., Davit, A., Sarotto, I., and Caderni, G. (2000) Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis 21: 1619-1622.
Triantafillidis, J. K., Nasioulas, G., and Kosmidis, P. A. (2009) Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res 29: 2727-2737.
Vargo, D., Doyle, R., and Floch, M. H. (1985) Colonic bacterial flora and serum cholesterol: alterations induced by dietary citrus pectin. Am J Gastroenterol 80: 361-364.
Velmurugan, B., Singh, R. P., Tyagi, A., and Agarwal, R. (2008) Inhibition of azoxymethane-induced colonic aberrant crypt foci formation by silibinin in male Fisher 344 rats. Cancer Prev Res (Phila Pa) 1: 376-384.
Vogelstein, B. and Kinzler, K. W. (1993) The multistep nature of cancer. Trends Genet 9: 138-141.
Walther, A., Johnstone, E., Swanton, C., Midgley, R., Tomlinson, I., and Kerr, D. (2009) Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer 9: 489-499.
Xu, L., Yang, Z. L., Li, P., and Zhou, Y. Q. (2009) Modulating effect of Hesperidin on experimental murine colitis induced by dextran sulfate sodium. Phytomedicine 16: 989-995.
Yoshiura, K., Kanai, Y., Ochiai, A., Shimoyama, Y., Sugimura, T., and Hirohashi, S. (1995) Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci U S A 92: 7416-7419.