[1] Kumar, S.; Pandey, A.K. Chemistry and biological activities of flavonoids: An overview. Sci. World J. 2013, 2013, 1-16.
[2] Singh, M.; Kaur, M.; Silakari, O. Flavones: an important scaffold for medicinal chemistry. Eur. J. Med. Chem. 2014, 84, 206-239.
[3] Lu, Y.H.; Zhang, C.W.; Bucheli, P.; Wei, D.Z. Citrus flavonoids in fruit and traditional Chinese medicinal food ingredients in China. Plant Foods Hum. Nutr. 2006, 61, 57-65.
[4] Li, S.M.; Wang, H.; Guo, L.M.; Zhao, H.; Ho, C.T. Chemistry and bioactivity of nobiletin and its metabolites. J. Funct. Foods. 2014, 6, 2-10.
[5] Li, S.M.; Pan, M.H.; Lo, C.Y.; Tan, D.; Wang, Y.; Shahidi, F.; Ho, C.T. Chemistry and health effects of polymethoxyflavones and hydroxylated polymethoxyflavones. J. Funct. Foods. 2009, 1, 2-12.
[6] Gao, Z.; Gao, W.; Zeng, S.L.; Li, P.; Liu, E.H. Chemical structures, bioactivities and molecular mechanisms of Citrus polymethoxyflavones. J. Funct. Foods. 2018, 40, 498-509.
[7] Nogata, Y.; Sakamoto, K.; Shiratsuchi, H.; Ishii, T.; Yano, M.; Ohta, H. Flavonoid composition of fruit tissues of Citrus species. Biosci. Biotechnol. Biochem. 2006, 70, 178-192.
[8] Du, Q.Z.; Chen, H. The methoxyflavones in Citrus reticulata Blanco cv. ponkan and their antiproliferative activity against cancer cells. Food Chem. 2010, 119, 567-572.
[9] Abe, S.; Fan, K.H.; Ho, C.T.; Ghai, G.; Yang, K. Chemopreventive effects of orange peel extract (OPE). II: OPE inhibits atypical hyperplastic lesions in rodent mammary gland. J. Med. Food. 2007, 10, 18-24.
[10] Cao, G.; Fu, Q.; Zhang, C.; Wang, H.; Chen, S.Z. Rapid characterization of 96 chemical constituents in Citri Reticulatae Folium (leaves of „Fuju‟) using HPLC-DAD-ESI-MSn. J. Chin. Pharm. Sci. 2016, 25, 91-110.
[11] Yu, X.; Sun, S.; Guo, Y.Y.; Liu, Y.; Yang, D.Y.; Li, G.Y.; Lü, S. Citri Reticulatae Pericarpium (Chenpi): Botany, ethnopharmacology, phytochemistry, and pharmacology of a frequently used traditional Chinese medicine. J. Ethnopharmacol. 2018, 220, 265-282.
[12] Li, S.M.; Pan, M.H.; Lo, C.Y.; Tan, D.; Wang, Y.; Shahidi, F.; Ho, C.T. Chemistry and health effects of polymethoxyflavones and hydroxylated polymethoxyflavones. J. Funct. Foods. 2009, 1, 2-12.
[13] Rawson, N.E.; Ho, C.T.; Li, S.M. Efficacious anti-cancer property of flavonoids from Citrus peels. Food Sci. Hum. Wellness. 2014, 3, 104-109.
[14] Wang, L.W.; Wang, J.H.; Fang, L.Y.; Zheng, Z.L.; Zhi, D.X.; Wang, S.Y.; Li, S.M.; Ho, C.T.; Zhao, H. Anticancer activities of Citrus peel polymethoxyflavones related to angiogenesis and others. Biomed. Res. Int. 2014, 2014, 453972.
[15] Walle, T.; Ta, N.; Kawamori, T.; Wen, X.; Tsuji, P.A.; Walle, U.K. Cancer chemopreventive properties of orally bioavailable flavonoids: methylated versus unmethylated flavones. Biochem. Pharmacol. 2007, 73, 1288-1296.
[16] Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394-424.
[17] Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA A Cancer J. Clin. 2018, 68, 7-30.
[18] Carey, L.A. Directed therapy of subtypes of triple-negative breast cancer. Oncologist. 2011, 16 Suppl 1, 71-78.
[19] Huang, H.; Li, L.F.; Shi, W.M.; Liu, H.; Yang, J.Q.; Yuan, X.L.; Wu, L.H. The multifunctional effects of nobiletin and its Metabolites In vivo and In vitro. Ev.id. Based Complement. Alternat. Med. 2016, 2016, 1-14.
[20] Braidy, N.; Behzad, S.; Habtemariam, S.; Ahmed, T.; Daglia, M.; Nabavi, S.M.; Sobarzo-Sanchez, E.; Nabavi, S.F. Neuroprotective effects of Citrus fruit-derived flavonoids, nobiletin and tangeretin in Alzheimer‟s and Parkinson's disease. CNS Neurol. Disord. Drug Targets. 2017, 16, 387-397.
[21] Doogue, M.P.; Polasek, T.M. The ABCD of clinical pharmacokinetics. Ther. Adv. Drug Saf. 2013, 4, 5-7.
[22] Goh, J.X.H.; Tan, L.T.; Goh, J.K.; Chan, K.G.; Pusparajah, P.; Lee, L.H.; Goh, B.H. Nobiletin and derivatives: functional compounds from Citrus fruit peel for colon cancer chemoprevention. Cancers (Basel). 2019, 11, E867.
[23] Wen, X.; Walle, T. Methylated flavonoids have greatly improved intestinal absorption and metabolic stability. Drug Metab. Dispos. 2006, 34, 1786-1792.
[24] Kemperman, R.A.; Bolca, S.; Roger, L.C.; Vaughan, E.E. Novel approaches for analysing gut microbes and dietary polyphenols: challenges and opportunities. Microbiology. 2010, 156, 3224-3231.
[25] Singh, S.P.; Wahajuddin,, Tewari, D.; Patel, K.; Jain, G.K. Permeability determination and pharmacokinetic study of nobiletin in rat plasma and brain by validated high-performance liquid chromatography method. Fitoterapia. 2011, 82, 1206-1214.
[26] Kumar, A.; Devaraj, V.C.; Giri, K.C.; Giri, S.; Rajagopal, S.; Mullangi, R. Development and validation of a highly sensitive LC-MS/MS-ESI method for the determination of nobiletin in rat plasma: application to a pharmacokinetic study. Biomed. Chromatogr. 2012, 26, 1464-1471.
[27] Murakami, A.; Koshimizu, K.; Ohigashi, H.; Kuwahara, S.; Kuki, W.; Takahashi, Y.; Hosotani, K.; Kawahara, S.; Matsuoka, Y. Characteristic rat tissue accumulation of nobiletin, a chemopreventive polymethoxyflavonoid, in comparison with luteolin. Biofactors. 2002, 16, 73-82.
[28] Evans, M.; Sharma, P.; Guthrie, N. Bioavailability of Citrus polymethoxylated flavones and their biological role in metabolic syndrome and hyperlipidemia. Readings in Advanced Pharmacokinetics - Theory, Methods and Applications. InTech. 2012, 267-284.
[29] Hung, W.L.; Chang, W.S.; Lu, W.C.; Wei, G.J.; Wang, Y.; Ho, C.T.; Hwang, L.S. Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat. J. Food Drug Anal. 2018, 26, 849-857.
[30] Meiyanto, E.; Hermawan, A.; Junedi, S.; Fitriasari, A.; Susidarti, R.A. Nobiletin increased cytotoxic activity of doxorubicin on MCF-7 cells but not on T47D cells. Int. J. Phytomed. 2011, 3, 129-137.
[31] Surichan, S.; Androutsopoulos, V.P.; Sifakis, S.; Koutala, E.; Tsatsakis, A.; Arroo, R.R.; Boarder, M.R. Bioactivation of the Citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells. Food Chem. Toxicol. 2012, 50, 3320-3328.
[32] Takeshima, M.; Ono, M.; Higuchi, T.; Chen, C.; Hara, T.; Nakano, S. Anti-proliferative and apoptosis-inducing activity of lycopene against three subtypes of human breast cancer cell lines. Cancer Sci. 2014, 105, 252-257.
[33] Surichan, S.; Arroo, R.R.; Ruparelia, K.; Tsatsakis, A.M.; Androutsopoulos, V.P. Nobiletin bioactivation in MDA-MB-468 breast cancer cells by cytochrome P450 CYP1 enzymes. Food Chem. Toxicol. 2018, 113, 228-235.
[34] Surichan, S.; Arroo, R.R.; Tsatsakis, A.M.; Androut-sopoulos, V.P. Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin. Toxicol. In Vitro. 2018, 50, 274-284.
[35] Fan, S.J.; Xu, H.F.; Liu, H.G.; Hu, Z.C.; Xiao, J.Y.; Liu, H. Inhibition of cancer cell growth by Tangeretin flavone in drug-resistant MDA-MB-231 human breast carcinoma cells is facilitated via targeting cell apoptosis, cell cycle phase distribution, cell invasion and activation of numerous caspases. J. BUON. 2019, 24, 1532-1537.
[36] Morley, K.L.; Ferguson, P.J.; Koropatnick, J. Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Lett. 2007, 251, 168-178.
[37] Baek, S.H.; Kim, S.M.; Nam, D.; Lee, J.H.; Ahn, K.S.; Choi, S.H.; Kim, S.H.; Shim, B.S.; Chang, I.M.; Ahn, K.S. Antimetastatic effect of nobiletin through the down-regulation of CXC chemokine receptor type 4 and matrix metallopeptidase-9. Pharm. Biol. 2012, 50, 1210-1218.
[38] Sp, N.; Kang, D.; Joung, Y.; Park, J.; Kim, W.; Lee, H.; Song, K.D.; Park, Y.M.; Yang, Y. Nobiletin inhibits angiogenesis by regulating src/FAK/STAT3-mediated signaling through PXN in ER+ breast cancer cells. Int. J. Mol. Sci. 2017, 18, 935.
[39] Sp, N.; Kang, D.Y.; Kim, D.H.; Park, J.H.; Lee, H.G.; Kim, H.J.; Darvin, P.; Park, Y.M.; Yang, Y.M. Nobiletin inhibits CD36-dependent tumor angiogenesis, migration, invasion, and sphere formation through the Cd36/Stat3/nf-κb signaling Axis. Nutrients. 2018, 10, E772.
[40] Liu, J.L.; Wang, S.; Tian, S.Q.; He, Y.; Lou, H.; Yang, Z.J.; Kong, Y.C.; Cao, X.Y. Nobiletin inhibits breast cancer via p38 mitogen-activated protein kinase, nuclear transcription factor-κB, and nuclear factor erythroid 2-related factor 2 pathways in MCF-7 cells. Food Nutr. Res. 2018, 62, DOI:10.29219/fnr.v62.1323.
[41] Kerdelhué, B.; Forest, C.; Coumoul, X. Dimethyl-benz(a)anthracene: a mammary carcinogen and a neuroendocrine disruptor. Biochim. Open. 2016, 3, 49-55.
[42] van Slambrouck, S.; Parmar, V.S.; Sharma, S.K.; De Bondt, B.; Foré, F.; Coopman, P.; Vanhoecke, B.W.; Boterberg, T.; Depypere, H.T.; Leclercq, G.; Bracke, M.E. Tangeretin inhibits extracellular-signal-regulated kinase (ERK) phosphorylation. FEBS Lett. 2005, 579, 1665-1669.
[43] Meiyanto, E.; Fitriasari, A.; Hermawan, A.; Junedi, S.; Susidarti, R.A. The improvement of doxorubicin activity on breast cancer cell lines by tangeretin through cell cycle modulation. Orient. Pharm. Exp. Med. 2011, 11, 183-190.
[44] Lakshmi, A.; Subramanian, S.P. Tangeretin ameliorates oxidative stress in the renal tissues of rats with experimental breast cancer induced by 7, 12-dimethylbenz[a]anthracene. Toxicol. Lett. 2014, 229, 333-348.
[45] Lakshmi, A.; Subramanian, S. Chemotherapeutic effect of tangeretin, a polymethoxylated flavone studied in 7, 12-dimethylbenz(a)anthracene induced mammary carcinoma in experimental rats. Biochimie. 2014, 99, 96-109.
[46] Arivazhagan, L.; Sorimuthu Pillai, S. Tangeretin, a Citrus pentamethoxy flavone, exerts cytostatic effect via p53/p21 up-regulation and suppresses metastasis in 7, 12-dimethylbenz(a)anthracene-induced rat mammary carcinoma. J. Nutr. Biochem. 2014, 25, 1140-1153.
[47] Arivazhagan, L.; Subramanian, S.P. Tangeretin, a Citrus flavonoid attenuates oxidative stress and protects hepatocellular architecture in rats with 7, 12-dimethylbenz(a)anthracene induced experimental mammary carcinoma. J. Funct. Foods. 2015, 15, 339-353.
[48] Periyasamy, K.; Baskaran, K.; Ilakkia, A.; Vanitha, K.; Selvaraj, S.; Sakthisekaran, D. Antitumor efficacy of tangeretin by targeting the oxidative stress mediated on 7, 12-dimethylbenz(a) anthracene-induced proliferative breast cancer in Sprague-Dawley rats. Cancer Chemother. Pharmacol. 2015, 75, 263-272.
[49] Periyasamy, K.; Sivabalan, V.; Baskaran, K.; Kasthuri, K.; Sakthisekaran, D. Cellular metabolic energy modulation by tangeretin in 7, 12-dimethylbenz(a) anthracene-induced breast cancer. J. Biomed. Res. 2016, 30, 134-141.
[50] Yoshimizu, N.; Otani, Y.; Saikawa, Y.; Kubota, T.; Yoshida, M.; Furukawa, T.; Kumai, K.; Kameyama, K.; Fujii, M.; Yano, M.; Sato, T.; Ito, A.; Kitajima, M. Anti-tumour effects of nobiletin, a Citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment. Pharmacol. Ther. 2004, 20, 95-101.
[51] Moon, J.Y.; Cho, S.K. Nobiletin induces protective autophagy accompanied by ER-stress mediated apoptosis in human gastric cancer SNU-16 cells. Molecules. 2016, 21, E914.
[52] Chen, P.Y.; Chen, Y.T.; Gao, W.Y.; Wu, M.J.; Yen, J.H. Nobiletin down-regulates c-KIT gene expression and exerts antileukemic effects on human acute myeloid leukemia cells. J. Agric. Food Chem. 2018, 66, 13423-13434.
[53] Luo, G.; Guan, X.L.; Zhou, L.M. Apoptotic effect of Citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer Biol. Ther. 2008, 7, 966-973.
[54] Zheng, G.D.; Hu, P.J.; Chao, Y.X.; Zhou, Y.; Yang, X.J.; Chen, B.Z.; Yu, X.Y.; Cai, Y. Nobiletin induces growth inhibition and apoptosis in human nasopharyngeal carcinoma C666-1 cells through regulating PARP-2/SIRT1/AMPK signaling pathway. Food Sci. Nutr. 2019, 7, 1104-1112.
[55] Cheng, H.L.; Hsieh, M.J.; Yang, J.S.; Lin, C.W.; Lue, K.H.; Lu, K.H.; Yang, S.F. Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression. Oncotarget. 2016, 7, 35208-35223.
[56] Chen, J.C.; Chen, A.Y.; Huang, H.Z.; Ye, X.Q.; Rollyson, W.D.; Perry, H.E.; Brown, K.C.; Rojanasakul, Y.; Rankin, G.O.; Dasgupta, P.; Chen, Y.C. The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway. Int. J. Oncol. 2015, 46, 2629-2638.
[57] Guney Eskiler, G.; Deveci, A.O.; Bilir, C.; Kaleli, S. Synergistic effects of nobiletin and sorafenib combination on metastatic prostate cancer cells. Nutr. Cancer. 2019, 71, 1299-1312.
[58] Sousa, D.P.; Pojo, M.; Pinto, A.T.; Leite, V.; Serra, A.T.; Cavaco, B.M. Nobiletin alone or in combination with cisplatin decreases the viability of anaplastic thyroid cancer cell lines. Nutr. Cancer. 2020, 72, 352-363.
[59] Ting, Y.W.; Chiou, Y.S.; Pan, M.H.; Ho, C.T.; Huang, Q.R. In vitro and in vivo anti-cancer activity of tangeretin against colorectal cancer was enhanced by emulsion-based delivery system. J. Funct. Foods. 2015, 15, 264-273.
[60] Dong, Y.; Cao, A.L.; Shi, J.R.; Yin, P.H.; Wang, L.; Ji, G.; Xie, J.Q.; Wu, D.Z. Tangeretin, a Citrus polymethoxy flavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways. Oncol. Rep. 2014, 31, 1788-1794.
[61] Zhang, X.K.; Zheng, L.M.; Sun, Y.G.; Wang, T.X.; Wang, B.C. Tangeretin enhances radiosensitivity and inhibits the radiation-induced epithelial-mesenchymal transition of gastric cancer cells. Oncol. Rep. 2015, 34, 302-310.
[62] Yumnam, S.; Raha, S.; Kim, S.; Venkatarame Gowda Saralamma, V.; Lee, H.; Ha, S.; Heo, J.; Lee, S.; Kim, E.; Lee, W.; Kim, J.; Kim, G. Identification of a novel biomarker in tangeretin-induced cell death in AGS human gastric cancer cells. Oncol. Rep. 2018, 40, 3249−3260.
[63] Ma, L.L.; Wang, D.W.; Yu, X.D.; Zhou, Y.L. Tangeretin induces cell cycle arrest and apoptosis through upregulation of PTEN expression in glioma cells. Biomed. Pharmacother. 2016, 81, 491-496.
[64] Hirano, T.; Abe, K.; Gotoh, M.; Oka, K. Citrus flavone tangeretin inhibits leukaemic HL-60 cell growth partially through induction of apoptosis with less cytotoxicity on normal lymphocytes. Br. J. Cancer 1995, 72, 1380-1388.
[65] Zheng, J.; Shao, Y.Q.; Jiang, Y.; Chen, F.; Liu, S.L.; Yu, N.H.; Zhang, D.D.; Liu, X.H.; Zou, L.H. Tangeretin inhibits hepatocellular carcinoma proliferation and migration by promoting autophagy-related BECLIN1. Cancer Manag. Res. 2019, 11, 5231-5242.
[66] Chen, K.H.; Weng, M.S.; Lin, J.K. 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. 2007, 73, 215-227.
[67] Li, Y.R.; Li, S.M.; Ho, C.T.; Chang, Y.H.; Tan, K.T.; Chung, T.W.; Wang, B.Y.; Chen, Y.K.; Lin, C.C. Tangeretin derivative, 5-acetyloxy-6, 7, 8, 4'-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo. Cancer Biol. Ther. 2016, 17, 48-64.
[68] Arafa, E.S.A.; Zhu, Q.Z.; Barakat, B.M.; Wani, G.; Zhao, Q.; El-Mahdy, M.A.; Wani, A.A. Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway. Cancer Res. 2009, 69, 8910-8917.
[69] Zhu, W.B.; Xiao, N.; Liu, X.J. Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. Oncol. Lett. 2018, 15, 433-440.
[70] Kawaii, S.; Tomono, Y.; Katase, E.; Ogawa, K.; Yano, M. Quantitation of flavonoid constituents in Citrus fruits. J. Agric. Food Chem. 1999, 47, 3565-3571.
[71] Manthey, J.A.; Guthrie, N. Antiproliferative activities of Citrus flavonoids against six human cancer cell lines. J. Agric. Food Chem. 2002, 50, 5837-5843.
[72] Li, S.M.; Pan, M.H.; Lai, C.S.; Lo, C.Y.; Dushenkov, S.; Ho, C.T. Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines. Bioorg. Med. Chem. 2007, 15, 3381-3389.
[73] Qiu, P.J.; Dong, P.; Guan, H.S.; Li, S.M.; Ho, C.T.; Pan, M.H.; McClements, D.J.; Xiao, H. Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Mol. Nutr. Food Res. 2010, 54 Suppl 2, S244-S252.
[74] Charoensinphon, N.; Qiu, P.J.; Dong, P.; Zheng, J.K.; Ngauv, P.; Cao, Y.; Li, S.M.; Ho, C.T.; Xiao, H. 5-Demethyltangeretin inhibits human nonsmall cell lung cancer cell growth by inducing G2/M cell cycle arrest and apoptosis. Mol. Nutr. Food Res. 2013, 57, 2103-2111.
[75] Manthey, J.A.; Cesar, T.B.; Jackson, E.; Mertens-Talcott, S. Pharmacokinetic study of nobiletin and tangeretin in rat serum by high-performance liquid chromatography-electrospray ionization-mass spectrometry. J. Agric. Food Chem. 2011, 59, 145-151. |