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化学进展 2020, Vol. 32 Issue (12): 1869-1878 DOI: 10.7536/PC200420   后一篇

• 综述 •

靶向葡萄糖转运蛋白(GLUTs)抗癌药物的开发

孙子茹1, 刘胜男1,2,**(), 高清志1,**()   

  1. 1 天津大学药物科学与技术学院 天津市现代药物传递及功能高效化重点实验室 天津 300072
    2 天津大学分子+研究院 天津 300072
  • 收稿日期:2020-04-19 修回日期:2020-05-06 出版日期:2021-10-15 发布日期:2021-01-15
  • 通讯作者: 刘胜男, 高清志
  • 作者简介:
    ** Corresponding author e-mail: (Shengnan Liu); (Qingzhi Gao)
  • 基金资助:
    国家自然科学基金项目(No. 21772144)

Development of Anticancer Drugs Targeting Glucose Transporters(GLUTs)

Ziru Sun1, Shengnan Liu1,2,**(), Qingzhi Gao1,**()   

  1. 1 School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin University, Tianjin 300072, China
    2 Institute of Molecular Plus, Tianjin University, Tianjin 300072, China
  • Received:2020-04-19 Revised:2020-05-06 Online:2021-10-15 Published:2021-01-15
  • Contact: Shengnan Liu, Qingzhi Gao
  • Supported by:
    the National Natural Science Foundation of China(No. 21772144)

基于肿瘤细胞与正常细胞葡萄糖代谢差异的肿瘤沃伯格效应,是目前新型靶向抗肿瘤药物开发的研究热点之一。本文以沃伯格效应的代谢特征和特异性生物标识物为出发点,从靶向葡萄糖转运蛋白(GLUTs)生物靶点和利用肿瘤葡萄糖代谢亢进的生物特征这两个层面,综述了具有代表性的GLUTs抑制剂以及GLUTs靶向型糖偶联抗肿瘤药物的研发现状,讨论并解析通过靶向沃伯格效应开发抗肿瘤药物的设计思路、实施策略与推广前景。

Increased glycolysis in malignant tumors has been one of the hallmarks and biotargets of tumor targeting that enable the design and development of novel targeted therapy agents. In this review, by focusing on the Warburg effect-targeted drug discovery and the unique concepts for development of glucose transporters(GLUTs)-targeted anticancer agents, we examine the current scenario with a brief introduction of anticancer GLUTs inhibitors and glycoconjugated antitumor examples, to provide an overview of studies of the Warburg effect-targeted anticancer drug development, the design strategy and useful perspectives for new-generation of targeted chemotherapeutic agents.

Contents

1 Introduction

2 Glucose transporters

3 Research status of anticancer targeted drugs utilizing the Warburg effect

3.1 GLUTs inhibitors

3.2 Glycoconjugates for tumor targeting

4 Conclusion and outlook

()
图1 (a)正常细胞代谢示意图;(b)癌细胞代谢示意图
Fig.1 (a) Schematic diagram of normal cell metabolism.(b) Schematic diagram of cancer cell metabolism
图2 代表性的天然产物类GLUTs抑制剂
Fig.2 Representative natural compounds as GLUT inhibitors
图3 处于临床前体外研究阶段的代表性GLUTs抑制剂: (a)GLUT1抑制剂;(b)GLUT1和GLUT3抑制剂;(c)GLUT4抑制剂;(d)GLUT5抑制剂
Fig.3 Representative of GLUTs inhibitors in preclinical in vitro studies, (a) GLUT1 inhibitors,(b) GLUT1 and GLUT3 inhibitor,(c) GLUT4 inhibitor,(d) GLUT5 inhibitor
图4 处于临床前体内研究阶段的代表性GLUTs抑制剂
Fig.4 Representative of GLUTs inhibitors in preclinical in vivo studies
图5 代表性的葡萄糖类似物
Fig.5 Representative glucose analogs
表1 2-DG在癌症中的临床试验研究[57 ? ?~60]
Table 1 Several cancer clinical trials with 2-DG[57 ? ?~60]
图6 代表性的糖偶联化合物
Fig.6 Representative glycoconjugates
[1]
Warburg O, Wind F, Negelein E. J. Gen. Physiol., 1927, 8:519.
[2]
Liberti M V, Locasale J W. Trends Biochem. Sci., 2016, 41(3):211.
[3]
Heiden M G V, Cantley L C, Thompson C B. Science, 2009, 324:1029.
[4]
Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, Yan N. Nature, 2014, 510(7503):121.
[5]
Deng D, Sun P, Yan C, Ke M, Jiang X, Xiong L, Ren W, Hirata K, Yamamoto M, Fan S, Yan N. Nature, 2015, 526(7573):391.
[6]
Shi Y L, Liu S N, Ahmad S, Gao Q Z. Curr. Trends Med. Chem., 2018, 18(6):454.
[7]
Grover-McKay M, Walsh S A, Seftor E A, Thomas P A, Hendrix M J. Pathol. Oncol. Res., 1998, 4(2): 115.
[8]
Cruz M D, Ledbetter S, Chowdhury S, Tiwari A K, Momi N, Wali R K, Bliss C, Huang C, Lichtenstein D, Bhattacharya S, Varma-Wilson A, Backman V, Roy H K. Oncotarget, 2017, 8(13):20543.
[9]
Alves V A, Pinheiro C, Morais-Santos F, Felipe-Silva A, Longatto A, Baltazar F. World J. Gastroenterol., 2014, 20(33):11780.
[10]
Yan S Y, Wang Y Q, Chen M M, Li G M, Fan J G. Int. J. Mol. Sci., 2015, 16(7): 16144.
[11]
Zhao H Y, Sun J, Shao J S, Zou Z F, Qiu X S, Wang E H, Wu G P. J. Cancer, 2019, 10(20): 4989.
[12]
Bhattacharya I S, Sharabiani M T A, Alonzi R, Hoskin P J. Radiother. Oncol., 2019, 137:38.
[13]
Chen Y H, Song Y, Yu Y L, Cheng W, Tong X. Oncol. Lett., 2019, 17(6):5441.
[14]
Pizzuti L, Sergi D, Mandoj C, Antoniani B, Sperati F, Chirico A, Di Lauro L, Valle M, Garofalo A, Vizza E, Corrado G, Tomao F, Rinaldi M, Carpano S, Maugeri-Sacca M, Conti L, Digiesi G, Marchetti P, De Maria R, Giordano A, Barba M, Carosi M A, Vici P. J. Cell. Physiol., 2018, 233(2): 1396.
[15]
Chen J, Cao L, Li Z Q, Li Y W. Hum. Cell, 2019, 32(2): 193.
[16]
Sukeda A, Nakamura Y, Nishida Y, Kojima M, Gotohda N, Akimoto T, Ochiai A. Pancreas, 2019, 48(8):1102.
[17]
Koch A, Ebert E V, Seitz T, Dietrich P, Berneburg M, Bosserhoff A, Hellerbrand C. Pathol., Res. Pract., 2020, 216(1): 152752.
[18]
Thorens B. Diabetologia, 2015, 58(2): 221.
[19]
Hinden L, Udi S, Drori A, Gammal A, Nemirovski A, Hadar R, Baraghithy S, Permyakova A, Geron M, Cohen M, Tsytkin-Kirschenzweig S, Riahi Y, Leibowitz G, Nahmias Y, Priel A, Tam J. J. Am. Soc. Nephrol., 2018, 29(2): 434.
[20]
Medina A, Parween S, Ullsten S, Vishnu N, Siu Y T, Quach M, Bennet H, Balhuizen A, Akesson L, Wierup N, Carlsson P O, Ahlgren U, Lernmark A, Fex M. Diabetologia, 2018, 61(4):896.
[21]
Yamamoto T, Seino Y, Fukumoto H, Koh G, Yano H, Inagaki N, Yamada Y, Inoue K, Manabe T, Imura H. Biochem. Biophys. Res. Commun., 1990, 170(1): 223.
[22]
Brown R S, Wahl R L. Cancer, 1993, 72(10): 2979.
[23]
Noguchi Y, Marat D, Saito A, Yoshikawa T, Doi C, Fukuzawa K, Tsuburaya A, Satoh S, Ito T. Hepato-gastroenterology, 1999, 46(28):2683.
[24]
陆国华( Lu G H), 钟秀君( Zhong X J), 丁伟(Ding W), 周建英(Zhou J Y). 浙江大学学报(医学版)( Zhejiang Daxue Xuebao, Yixueban), 2008, 37(2): 176.
[25]
Fei X, Qi M L, Wu B, Song Y S, Wang Y P, Li T T. FEBS Lett., 2012, 586(4):392.
[26]
Ayala F R R, Rocha R M, Carvalho K C, Carvalho A L, da Cunha I W, Lourenco S V, Soares F A. Molecules, 2010, 15(4):2374.
[27]
Starska K, Forma E, Jozwiak P, Brys M, Lewy-Trenda I, Brzezinska-Blaszczyk E, Krzeslak A. Tumor Biol., 2015, 36(4):2309.
[28]
Karnieli E, Armoni M. Am. J. Physiol.: Endocrinol. MeTab., 2008, 295(1): E38.
[29]
LeFevre P G, Marshall J K. J. Biol. Chem., 1959, 234(11): 3022.
[30]
Van Goietsenoven G, Mathieu V, Andolfi A, Cimmino A, Lefranc F, Kiss R, Evidente A.. Planta Med., 2011, 77(07): 711.
[31]
Choi B H, Park J A, Kim K R, Lee G I, Lee Y T, Choe H, Ko S H, Kim M H, Seo Y H, Kwak Y G. Am. J. Physiol.: Cell Physiol., 2005, 289(2): C425.
[32]
Bielanska J, Hernandez-Losa J, Perez-Verdaguer M, Moline T, Somoza R, Cajal S R Y, Condom E, Ferreres J C, Felipe A. Curr. Cancer Drug Targets, 2009, 9(8):904.
[33]
Khusbu F Y, Zhou X, Roy M, Chen F Z, Cao Q, Chen H C. Int. J. Biochem. Cell Biol., 2020, 118:105644.
[34]
Zambrano A, Molt M, Uribe E, Salas M. Int. J. Mol. Sci., 2019, 20(13):3374.
[35]
Lin S T, Tu S H, Yang P S, Hsu S P, Lee W H, Ho C T, Wu C H, Lai Y H, Chen M Y, Chen L C. J. Agric. Food Chem., 2016, 64(36):6826.
[36]
Wu K H, Ho C T, Chen Z F, Chen L C, Whang-Peng J, Lin T N, Ho Y S. J. Food Drug Anal., 2018, 26(1): 221.
[37]
Sajadimajd S, Bahramsoltani R, Iranpanah A, Kumar Patra J, Das G, Gouda S, Rahimi R, Rezaeiamiri E, Cao H, Giampieri F, Battino M, Tundis R, Campos M G, Farzaei M H, Xiao J B. Pharmacol. Res., 2019:104584.
[38]
Yang J, Wei S, Wang D S, Wang Y C, Kulp S K, Chen C S. J. Med. Chem., 2008, 51(7): 2100.
[39]
Wang D S, Chu P C, Yang C N, Yan R B, Chuang Y C, Kulp S K, Chen C S. J. Med. Chem., 2012, 55(8):3827.
[40]
Ung P M U, Song W X, Cheng L L, Zhao X B, Hu H L, Chen L G, Schlessinger A. ACS Chem. Biol., 2016, 11(7): 1908.
[41]
Granchi C, Qian Y R, Lee H Y, Paterni I, Pasero C, Iegre J, Carlson K E, Tuccinardi T, Chen X Z, Katzenellenbogen J A, Hergenrother P J, Minutolo F. ChemMedChem, 2015, 10(11): 1892.
[42]
Karageorgis G, Reckzeh E S, Ceballos J, Schwalfenberg M, Sievers S, Ostermann C, Pahl A, Ziegler S, Waldmann H. Nat. Chem., 2018, 10(11): 1103.
[43]
Ceballos J, Schwalfenberg M, Karageorgis G, Reckzeh E S, Sievers S, Ostermann C, Pahl A, Sellstedt M, Nowacki J, Corrales M A C, Wilke J, Laraia L, Tschapalda K, Metz M, Sehr D A, Brand S, Winklhofer K, Janning P, Ziegler S, Waldmann H. Angew. Chem., Int. Ed., 2019, 58(47): 17016.
[44]
Wei C Y, Bajpai R, Sharma H, Heitmeier M, Jain A D, Matulis S M, Nooka A K, Mishra R K, Hruz P W, Schiltz G E, Shanmugam M. Eur. J. Med. Chem., 2017, 139:573.
[45]
Thompson A M G, Ursu O, Babkin P, Iancu C V, Whang A, Oprea T I, Choe J Y. Sci. Rep., 2016, 6(1): 1.
[46]
Liu Y, Cao Y Y, Zhang W H, Bergmeier S, Qian Y R, Akbar H, Colvin R, Ding J, Tong L Y, Wu S Y, Hines J, Chen X Z. Mol. Cancer Ther., 2012, 11(8):1672.
[47]
Liu Y, Zhang W H, Cao Y Y, Liu Y, Bergmeier S, Chen X Z. Cancer Lett., 2010, 298(2): 176.
[48]
Chan D A, Sutphin P D, Nguyen P, Turcotte S, Lai E W, Banh A, Reynolds G E, Chi J T, Wu J, Solow-Cordero D E, Bonnet M, Flanagan J U, Bouley D M, Graves E E, Denny W A. Hay M P, Giaccia A J. Sci. Transl. Med., 2011, 3(94):94ra70.
[49]
Ma Y B, Wang W, Idowu M O, Oh U, Wang X Y, Temkin S M, Fang X J. Cancers, 2019, 11(1): 33.
[50]
Siebeneicher H, Cleve A, Rehwinkel H, Neuhaus R, Heisler I, Muller T, Bauser M, Buchmann B. ChemMedChem, 2016, 11(20): 2261.
[51]
Kang S A, O'Neill D J, Machl A W, Lumpkin C J, Galda S N, Sengupta S, Mahoney S J, Howell J J, Molz L, Hahm S, Vlasuk G P, Saiah E. Cell Chem. Biol., 2019, 26(9):1203.
[52]
Siebeneicher H, Bauser M, Buchmann B, Heisler I, Muller T, Neuhaus R, Rehwinkel H, Telser J, Zorn L. Bioorg. Med. Chem. Lett., 2016, 26(7): 1732.
[53]
Reckzeh E S, Karageorgis G, Schwalfenberg M, Ceballos J, Nowacki J, Stroet M C M, Binici A, Knauer L, Brand S, Choidas A, Strohmann C, Ziegler S, Waldmann H. Cell Chem. Biol., 2019, 26(9):1214.
[54]
Pajak B, Siwiak E, Sołtyka M, Priebe A, Zielinski R, Fokt I, Ziemniak M, Jaskiewicz A, Borowski R, Domoradzki T, Priebe W. Int. J. Mol. Sci., 2020, 21(1): 234.
[55]
Rohren E M, Turkington T G, Coleman R E. Radiol., 2004, 231(2): 305.
[56]
Millon S R, Ostrander J H, Brown J Q, Raheja A, Seewaldt V L, Ramanujam N. Breast Cancer Res. Treat., 2011, 126(1): 55.
[57]
Singh D, Banerji A K, Dwarakanath B S, Tripathi R P, Gupta J P, Mathew T L, Ravindranath T, Jain V. Strahlenther. Onkol., 2005, 181(8):507.
[58]
Mohanti B K, Rath G K, Anantha N, Kannan V, Das B S, Chandramouli B A, Banerjee A K, Das S, Jena A, Ravichandran R, Sahi U P, Kumar R, Kapoor N, Kalia V K, Dwarakanath B S, Jain V. Int. J. Radiat. Oncol. Biol. Phys., 1996, 35(1): 103.
[59]
Stein M, Lin H X, Jeyamohan C, Dvorzhinski D, Gounder M, Bray K, Eddy S, Goodin S, White E, DiPaola R S. Prostate, 2010, 70(13):1388.
[60]
Raez L E, Papadopoulos K, Ricart A D, Chiorean E G, DiPaola R S, Stein M N, Lima C M R, Schlesselman J J, Tolba K, Langmuir V K, Kroll S, Jung D T, Kurtoglu M, Rosenblatt J, Lampidis T J. Cancer Chemother. Pharmacol., 2013, 71(2): 523.
[61]
Pohl J, Bertram B, Hilgard P, Nowrousian M R, Stuben J, Wiessler M. Cancer Chemother. Pharmacol., 1995, 35(5):364.
[62]
Stüben J, Port R, Bertram B, Bollow U, Hull W E, Schaper M, Pohl J, Wiessler M. Cancer Chemother. Pharmacol., 1996, 38(4):355.
[63]
Bishop J, Murray R, Webster L, Pitt P, Stokes K, Fennessy A, Olver I, Leber G. Cancer Chemother. Pharmacol., 1992, 30(3):174.
[64]
Buchanan M K, Needham C N, Neill N E, White M C, Kelly C B, Mastro-Kishton K, Chauvigne-Hines L M, Goodwin T J, McIver A L, Bartolotti L J, Frampton A R, Bourdelais A J, Varadarajan S. Biochemistry, 2017, 56(2): 421.
[65]
Murray-Lyon I M, Eddleston A L, Williams R, Brown M, Hogbin B M, Bennett A, Edwards J C, Taylor K W. Lancet, 1968, 292(7574):895.
[66]
Halmos T, Santarromana M, Antonakis K, Scherman D. Eur. J. Pharmacol., 1996, 318(2/3):477.
[67]
Mandai T, Okumoto H, Oshitari T, Nakanishi K, Mikuni K, Hara K, Hara K, Iwatani W, Amano T, Nakamura K, Tsuchiya Y. Heterocycles. 2001, 54(2): 561.
[68]
Lin Y S, Tungpradit R, Sinchaikul S, An F M, Liu D Z, Phutrakul S, Chen S T. J. Med. Chem., 2008, 51(23):7428.
[69]
Liu D Z, Sinchaikul S, Reddy P V G, Chang M Y, Chen S T. Bioorg. Med. Chem. Lett., 2007, 17(3):617.
[70]
Cao J, Cui S, Li S, Du C, Tian J, Wan S, Qian Z, Gu Y, Chen W R, Wang G. Cancer Res., 2013, 73:1362.
[71]
Reinhard J, Hull W E, von der Lieth C W, Eichhorn U, Kliem H C, Kaina B, Wiessler M. J. Med. Chem., 2001, 44(24):4050.
[72]
Guo J, Du C L, Shan L L, Zhu H Y, Xue B, Qian Z Y, Achilefu S, Gu Y Q. Contrast Media Mol. Imaging, 2012, 7(3):289.
[73]
Liu P X, Lu Y H, Gao X Q, Liu R, Zhang N D, Shi Y L, Wang Y Q, Wang S Q, Gao Q Z, Chem. Commun., 2013, 49:2421.
[74]
Mi Q, Ma Y R, Gao X Q, Liu R, Liu P X, Mi Y, Fu X G, Gao Q Z. J. Biomol. Struct. Dyn., 2016, 34(11): 2339.
[75]
Liu R, Fu Z, Zhao M, Gao X Q, Li H, Mi Q, Liu P X, Yang J N, Yao Z, Gao Q Z. Oncotarget., 2017, 8(24):39476.
[76]
Gao X Q, Liu S N, Shi Y L, Huang Z H, Mi Y, Mi Q, Yang J N, Gao Q Z. Eur. J. Med. Chem., 2017, 125:372.
[77]
Quan L, Lin Z T, Lin Y B, Wei Y C, Lei L, Li Y X, Tan G J, Xiao M, Wu T F. J. Mol. Struct., 2020, 1203:127361.
[78]
Patra M, Awuah S G, Lippard S J. J. Am. Chem. Soc., 2016, 138(38):12541.
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