Original articles
Senling Feng, Huifang Zhou, Deyan Wu, Dechong Zheng, Biao Qu, Ruiming Liu, Chen Zhang, Zhe Li, Ying Xie, Hai-Bin Luo. Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 327-343

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents
Senling Fenga, Huifang Zhoub, Deyan Wub, Dechong Zhenga, Biao Qua, Ruiming Liua, Chen Zhangb, Zhe Lib, Ying Xiea, Hai-Bin Luob
a School of Pharmacy, State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China;
b School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Abstract:
Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.
Key words:    Nobiletin    Cancer multidrug resistance    Mechanism    Nobiletin    P-gp inhibition    Reversal agents    Solubility   
Received: 2019-04-07     Revised: 2019-07-05
DOI: 10.1016/j.apsb.2019.07.007
Funds: This work was supported by National Key R&D Program of China (2017YFB0202600), Macao Science and Technology Development Fund, Macau Special Administrative Region (003/2017/A1 to Ying Xie, China), National Natural Science Foundation of China (21572279, 21877134, 81602955 and 81703341), Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2016, China).
Corresponding author: Ying Xie, Hai-Bin Luo     Email:yxie@must.edu.mo;luohb77@mail.sysu.edu.cn
Author description:
Service
PDF(KB) Free
Print
0
Authors
Senling Feng
Huifang Zhou
Deyan Wu
Dechong Zheng
Biao Qu
Ruiming Liu
Chen Zhang
Zhe Li
Ying Xie
Hai-Bin Luo

References:
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, 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.
2. Alfarouk KO, Stock CM, Taylor S, Walsh M, Muddathir AK, Verduzco D, et al. Resistance to cancer chemotherapy:failure in drug response from ADME to P-gp. Cancer Cell Int 2015;15:71.
3. Elshimali YI, Wu Y, Khaddour H, Wu Y, Gradinaru D, Sukhija H, et al. Optimization of cancer treatment through overcoming drug resistance. J Cancer Res Oncobiol 2018;1:107.
4. Callaghan R, Luk F, Bebawy M. Inhibition of the multidrug resistance pglycoprotein:time for a change of strategy?. Drug Metab Dispos 2014; 42:623-31.
5. Zhang H, Huang L, Tao L, Zhang J, Wang F, Zhang X, et al. Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression. Acta Pharm Sin B 2019;9:516-25.
6. Chang L, Xiao M, Yang L, Wang S, Wang SQ, Bender A, et al. Discovery of a non-toxic[1,2,4] triazolo[1,5-a]pyrimidin-7-one (WS-10) that modulates ABCB1-mediated multidrug resistance (MDR). Bioorg Med Chem 2018;26:5974-85.
7. Wen Y, Zhao R, Gupta P, Fan Y, Zhang Y, Huang Z, et al. The epigallocatechin gallate derivative Y6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo. Acta Pharm Sin B 2019;9:316-23.
8. Zhang L, Zhang X, Zhang C, Bai X, Zhang J, Zhao X, et al. Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo. Brain Res 2016;1636:130-41.
9. Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba T, Koshimizu K, et al. Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res 2000;60:5059-66.
10. Ma W, Feng S, Yao X, Yuan Z, Liu L, Xie Y. Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells. Sci Rep 2015;5:18789.
11. Onoue S, Nakamura T, Uchida A, Ogawa K, Yuminoki K, Hashimoto N, et al. Physicochemical and biopharmaceutical characterization of amorphous solid dispersion of nobiletin, a citrus polymethoxylated flavone, with improved hepatoprotective effects. Eur J Pharm Sci 2013;49:453-60.
12. Asakawa T, Hiza A, Nakayama M, Inai M, Oyama D, Koide H, et al. PET Imaging of nobiletin based on a practical total synthesis. Chem Commun 2011;47:2868-70.
13. Guo Y, Ji SZ, Chen C, Liu HW, Zhao JH, Zheng YL, et al. A ligandfree, powerful, and practical method for methoxylation of unactivated aryl bromides by use of the CuCl/HCOOMe/MeONa/MeOH system. Res Chem Intermed 2015;41:8651-64.
14. Yoshida M, Saito K, Fujino Y, Doi T. A concise synthesis of 3-aroylflavones via lewis base 9-azajulolidine-catalyzed tandem acyl transfer-cyclization. Chem Commun 2012;48:11796-8.
15. Rocha DH, Pinto DC, Silva AM. Synthesis and cyclisation studies of (E)-2-Aryl-1-methyl-3-styrylquinolin-4(1H)-ones. Tetrahedron 2015; 71:7717-21.
16. Wesołowska O, Wiśniewski J, Środa-Pomianek K, Bielawska-Pohl A, Paprocka M, Duś D, et al. Multidrug resistance reversal and apoptosis induction in human colon cancer cells by some flavonoids present in Citrus plants. J Nat Prod 2012;75:1896-902.
17. Martins IL, Charneira C, Gandin V, Da Silva JL, Justino GC, Telo JP, et al. Selenium-containing chrysin and quercetin derivatives:attractive scaffolds for cancer therapy. J Med Chem 2015;58:4250-65.
18. Hadjeri M, Barbier M, Ronot X, Mariotte AM, Boumendjel A, Boutonnat J. Modulation of P-glycoprotein-mediated multidrug resistance by flavonoid derivatives and analogues. J Med Chem 2003; 46:2125-31.
19. Vassileva V, Grant J, De Souza R, Allen C, Piquette-Miller M. Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model. Cancer Chemother Pharmacol 2007;60:907-14.
20. De Oliveira Júnior RG, Christiane Adrielly AF, Da Silva Almeida JR, Grougnet R, Thiéry V, Picot L. Sensitization of tumor cells to chemotherapy by natural products:a systematic review of preclinical data and molecular mechanisms. Fitoterapia 2018;129:383-400.
21. Huang H, Li L, Shi W, Liu H, Yang J, Yuan X, et al. The multifunctional effects of nobiletin and its metabolites in vivo and in vitro. Evid Based Complement Alternat Med 2016;2016:2918796.
22. Wu X, Song M, Rakariyatham K, Zheng J, Wang M, Xu F, et al. Inhibitory effects of 4'-demethylnobiletin, a metabolite of nobiletin, on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mouse ears. J Agric Food Chem 2015;63:10921-7.
Similar articles:
1.Yuanzhi He, Wei Zhang, Tao Guo, Guoqing Zhang, Wei Qin, Liu Zhang, Caifen Wang, Weifeng Zhu, Ming Yang, Xiaoxiao Hu, Vikramjeet Singh, Li Wu, Ruxandra Gref, Jiwen Zhang.Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan[J]. Acta Pharmaceutica Sinica B, 2019,9(1): 97-106