Human Galectin-1 and Its Inhibitors: Privileged Target for Cancer and HIV

Author(s): Narella Sridhar Goud, P.S. Lakshmi Soukya, Mahammad Ghouse, Daipule Komal, Ravi Alvala, Mallika Alvala*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 16 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Galectin 1(Gal-1), a β-galactoside binding mammalian lectin of 14KDa, is implicated in many signalling pathways, immune responses associated with cancer progression and immune disorders. Inhibition of human Gal-1 has been regarded as one of the potential therapeutic approaches for the treatment of cancer, as it plays a major role in tumour development and metastasis by modulating various biological functions viz. apoptosis, angiogenesis, migration, cell immune escape. Gal-1 is considered as a biomarker in diagnosis, prognosis and treatment condition. The overexpression of Gal-1 is well established and seen in many types of cancer progression like osteosarcoma, breast, lung, prostate, melanoma, etc. Gal-1 greatly accelerates the binding kinetics of HIV-1 to susceptible cells, leading to faster viral entry and a more robust viral replication by specific binding of CD4 cells. Hence, the Gal-1 is considered a promising molecular target for the development of new therapeutic drugs for cancer and HIV. The present review laid emphasis on structural insights and functional role of Gal-1 in the disease, current Gal-1 inhibitors and future prospects in the design of specific Gal-1 inhibitors.

Keywords: Galectin 1, cancer, HIV, Gal-1 inhibitors, apoptosis, glycoprotein.

(a)Barondes, S.H.; Cooper, D.N.; Gitt, M.A.; Leffler, H. Galectins. Structure and Function of a Large Family of Animal Lectins. J. Biol. Chem., 1994, 269(1), 20807-20810.
(b)Wu, M-H.; Chen, Y-L.; Lee, K-H.; Chang, C-C.; Cheng, T-M.; Wu, S-Y.; Tu, C-C.; Tsui, W-L. Glycosylation-Dependent Galectin-1/Neuropilin-1 Interactions Promote Liver Fibrosis through Activation of TGF-β- and PDGF-like Signals in Hepatic Stellate Cells. Sci. Rep., 2017, 7(1), 20807-20810.
Dings, R.; Miller, M.; Griffin, R.; Mayo, K. Galectins as molecular targets for therapeutic intervention. Intl. J. Mol. Sci., 2018, 19(1), 905.
David, M.; Piero, C. New druggable targets in the RAS pathway. Curr. Opin. Mol. Ther., 2010, 12(1), 6-, 674-683.
Cousin, J.; Cloninger, M. The role of Galectin-1 in cancer progression, and synthetic multivalent systems for the study of Galectin-1. Intl. J. Mol. Sci., 2016, 17(1), 1566.
Al-Obaidi, N.; Mohan, S.; Liang, S.; Zhao, Z.; Nayak, B.K.; Li, B.; Sriramarao, P.; Habib, S.L. Galectin-1 Is a new fibrosis protein in Type 1 and Type 2 diabetes. FASEB J., 2018, 33(1), 1-2.
Astorgues-Xerri, L.; Riveiro, M.E.; Tijeras-Raballand, A.; Serova, M.; Neuzillet, C.; Albert, S.; Raymond, E.; Faivre, S. Unraveling galectin-1 as a novel therapeutic target for cancer. Cancer Treat. Rev., 2014, 40(1), 307-319.
St-Pierre, C.; Manya, H.; Ouellet, M.; Clark, G.F.; Endo, T.; Tremblay, M.J.; Sato, S. Host-Soluble Galectin-1 promotes HIV-1 Replication through a direct interaction with Glycans of viral Gp120 and Host CD4. J. Virol., 2011, 85(1), 11742-11751.
Croci, D.O.; Salatino, M.; Rubinstein, N.; Cerliani, J.P.; Cavallin, L.E.; Leung, H.J.; Ouyang, J.; Ilarregui, J.M.; Toscano, M.A.; Domaica, C.I.; Croci, M.C.; Shipp, M.A.; Mesri, E.A.; Albini, A.; Rabinovich, G.A. Disrupting Galectin-1 interactions with N-Glycans suppresses Hypoxia-Driven angiogenesis and tumorigenesis in Kaposi’s sarcoma. J. Exp. Med., 2012, 209(11), 1985-2000.
Hosseini, Y.; Mollica, A.; Mirzaie, S. Structure-Based virtual screening efforts against HIV-1 reverse transcriptase to introduce the new potent non-nucleoside reverse transcriptase inhibitor. J. Mol. Struct., 2016, 1125(1), 592-600.
Miao, J-H.; Wang, S-Q.; Zhang, M-H.; Yu, F-B.; Zhang, L.; Yu, Z-X.; Kuang, Y. Knockdown of Galectin-1 suppresses the growth and invasion of osteosarcoma cells through inhibition of the MAPK/ERK Pathway. Oncol. Rep., 2014, 32(1), 1497-1504.
Dalotto-Moreno, T.; Croci, D.O.; Cerliani, J.P.; Martinez-Allo, V.C.; Dergan-Dylon, S.; Mendez-Huergo, S.P.; Stupirski, J.C.; Mazal, D.; Osinaga, E.; Toscano, M.A.; Sundblad, V.; Rabinovich, G.A.; Salatino, M. Targeting Galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res., 2013, 73(1), 1107-1117.
Kuo, P-L.; Huang, M-S.; Cheng, D-E.; Hung, J-Y.; Yang, C-J.; Chou, S-H. Lung Cancer-Derived Galectin-1 enhances tumorigenic potentiation of tumor-associated dendritic cells by expressing heparin-binding EGF-like growth factor. J. Biol. Chem., 2012, 287(1), 9753-9764.
Compagno, D.; Gentilini, L.D.; Jaworski, F.M.; Perez, I.G.; Contrufo, G.; Laderach, D.J. Glycans and galectins in prostate cancer biology, angiogenesis and metastasis. Glycobiology, 2014, 24(10), 899-906.
Huang, C-S.; Tang, S-J.; Chung, L-Y.; Yu, C-P.; Ho, J-Y.; Cha, T-L.; Hsieh, C-C.; Wang, H-H.; Sun, G-H.; Sun, K-H. Galectin-1 Upregulates CXCR4 to promote tumor progression and poor outcome in kidney cancer. J. Am. Soc. Nephrol., 2014, 25(7), 1486-1495.
Kim, H-J.; Do, I-G.; Jeon, H-K.; Cho, Y.J.; Park, Y.A.; Choi, J-J.; Sung, C.O.; Lee, Y-Y.; Choi, C.H.; Kim, T-J.; Kim, B-G.; Lee, J-W.; Bae, D-S. Galectin 1 expression is associated with tumor invasion and metastasis in stage IB to IIA cervical cancer. Hum. Pathol., 2013, 44(1), 62-68.
Mathieu, V.; de Lassalle, E.M.; Toelen, J.; Mohr, T.; Bellahcène, A.; Van Goietsenoven, G.; Verschuere, T.; Bouzin, C.; Debyser, Z.; De Vleeschouwer, S.; Van Gool, S.; Poirier, F.; Castronovo, V.; Kiss, R.; Feron, O. Galectin-1 in melanoma biology and related Neo-Angiogenesis processes. J. Invest. Dermatol., 2012, 132(9), 2245-2254.
Martinez-Bosch, N.; Barranco, L.E.; Orozco, C.A.; Moreno, M.; Visa, L.; Iglesias, M.; Oldfield, L.; Neoptolemos, J.P.; Greenhalf, W.; Earl, J.; Carrato, A.; Costello, E.; Navarro, P. Increased plasma levels of Galectin-1 in pancreatic cancer: Potential use as biomarker. Oncotarget, 2018, 9(68), 32984-32996.
Thijssen, V.L.; Heusschen, R.; Caers, J.; Griffioen, A.W. Galectin expression in cancer diagnosis and prognosis: A systematic review. Biochim. Biophys. Acta, 2015, 1855(2), 235-247.
Elola, M.T.; Chiesa, M.E.; Alberti, A.F.; Mordoh, J.; Fink, N.E. Galectin-1 receptors in different cell types. J. Biomed. Sci., 2005, 12(1), 13-29.
Sörme, P.; Kahl-Knutsson, B.; Huflejt, M.; Nilsson, U.J.; Leffler, H. Fluorescence polarization as an analytical tool to evaluate Galectin-Ligand interactions. Analyt. Biochem., 2004, 334(1), 36-47.
Wu, R.; Wu, T.; Wang, K.; Luo, S.; Chen, Z.; Fan, M.; Xue, D.; Lu, H.; Zhuang, Q.; Xu, X. Prognostic significance of Galectin-1 expression in patients with cancer: A meta-Analysis. Cancer Cell Intl., 2018, 18(1), 108.
Blanchard, H.; Bum-Erdene, K.; Bohari, M.H.; Yu, X. Galectin-1 inhibitors and their potential therapeutic applications: A patent review. Expert Opin. Ther. Pat., 2016, 26(5), 537-554.
López-Lucendo, M.F.; Solís, D.; André, S.; Hirabayashi, J.; Kasai, K.; Kaltner, H.; Gabius, H-J.; Romero, A. Growth-Regulatory Human Galectin-1: Crystallographic characterisation of the structural changes induced by Single-Site mutations and their impact on the thermodynamics of ligand binding. J. Mol. Biol., 2004, 343(4), 957-970.
Salomonsson, E.; Larumbe, A.; Tejler, J.; Tullberg, E.; Rydberg, H.; Sundin, A.; Khabut, A.; Frejd, T.; Lobsanov, Y.D.; Rini, J.M.; Nilsson, U.J.; Leffler, H. Monovalent interactions of Galectin-1. Biochemistry, 2010, 49(44), 9518-9532.
Leppänen, A.; Stowell, S.; Blixt, O.; Cummings, R.D. Dimeric Galectin-1 binds with high affinity to Alpha2,3-Sialylated and Non-Sialylated terminal N-Acetyllactosamine units on surface-bound extended glycans. J. Biol. Chem., 2005, 280(1), 5549-5562.
Cho, M.; Cummings, R.D. Characterization of monomeric forms of Galectin-1 Generated by Site-Directed mutagenesis. Biochemistry, 1996, 35(1), 13081-13088.
Kadoya, T.; Horie, H. Structural and functional studies of galectin-1: A novel axonal regeneration-promoting activity for Oxidized Galectin-1. Curr. Drug Targets, 2005, 6(1), 375-383.
Guardia, C.M.; Caramelo, J.J.; Trujillo, M.; Méndez-Huergo, S.P.; Radi, R.; Estrin, D.A.; Rabinovich, G.A. Structural basis of redox-dependent modulation of Galectin-1 dynamics and function. Glycobiology, 2014, 24(5), 428-441.
Echeverria, I.; Amzel, L.M. Disaccharide binding to Galectin-1: Free energy calculations and molecular recognition mechanism. Biophys. J., 2011, 100(9), 2283-2292.
Horlacher, T.; Oberli, M.A.; Werz, D.B.; Kröck, L.; Bufali, S.; Mishra, R.; Sobek, J.; Simons, K.; Hirashima, M.; Niki, T.; Seeberger, P.H. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chem. Bio. Chem., 2010, 11(1), 1563-1573.
Fischer, C.; Sanchez-Ruderisch, H.; Welzel, M.; Wiedenmann, B.; Sakai, T.; André, S.; Gabius, H-J.; Khachigian, L.; Detjen, K.M.; Rosewicz, S. Galectin-1 Interacts with the A5β1 fibronectin receptor to restrict carcinoma cell growth via Induction of P21 and P27. J. Bio. Chem.., 2005, 280(1), 37266-37277.
Le, Q-T.; Shi, G.; Cao, H.; Nelson, D.W.; Wang, Y.; Chen, E.Y.; Zhao, S.; Kong, C.; Richardson, D.; O’Byrne, K.J.; Giaccia, A.J.; Koong, A.C. Galectin-1: A link between tumor hypoxia and tumor immune privilege. J. Clin. Oncol., 2005, 23(35), 8932-8941.
Ito, K.; Scott, S.A.; Cutler, S.; Dong, L-F.; Neuzil, J.; Blanchard, H.; Ralph, S.J. Thiodigalactoside inhibits murine cancers by concurrently blocking effects of Galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress. Angiogenesis, 2011, 14, 293-307.
Ito, K.; Ralph, S.J. Inhibiting Galectin-1 Reduces murine lung metastasis with increased CD4+ and CD8+ T cells and reduced cancer cell adherence. Clin. Exp. Metastasis, 2012, 29(6), 561-572.
Dings, R.P.M.; Miller, M.C.; Nesmelova, I.; Astorgues-Xerri, L.; Kumar, N.; Serova, M.; Chen, X.; Raymond, E.; Hoye, T.R.; Mayo, K.H. Antitumor agent calixarene 0118 targets human Galectin-1 as an allosteric inhibitor of carbohydrate binding. J. Med. Chem., 2012, 55(11), 5121-5129.
Sirois, S.; Giguère, D.; Roy, R. A First QSAR model for galectin-3 glycomimetic inhibitors based on 3D docked structures. Med. Chem., 2006, 2(5), 481-489.
Salameh, B.A.; Leffler, H.; Nilsson, U.J. 3-(1,2,3-Triazol-1-Yl)-1-Thio-Galactosides as small, Efficient, and hydrolytically stable inhibitors of Galectin-3. Bioorg. Med. Chem. Lett., 2005, 15(14), 3344-3346.
Tejler, J.; Leffler, H.; Nilsson, U.J. Synthesis of O-Galactosyl Aldoximes as potent LacNAc-Mimetic Galectin-3 inhibitors. Bioorg. Med. Chem. Lett., 2005, 15(9), 2343-2345.
Cumpstey, I.; Carlsson, S.; Leffler, H.; Nilsson, U.J. Synthesis of a Phenyl Thio-β-d-Galactopyranoside library from 1,5-Difluoro-2,4-Dinitrobenzene: Discovery of efficient and selective monosaccharide inhibitors of Galectin-7. Org. Biomol. Chem., 2005, 3(10), 1922.
Salameh, B.A.; Sundin, A.; Leffler, H.; Nilsson, U.J. Thioureido N-Acetyllactosamine derivatives as potent Galectin-7 and 9N Inhibitors. Bioorg. Med. Chem., 2006, 14(4), 1215-1220.
Cumpstey, I.; Sundin, A.; Leffler, H.; Nilsson, U.J. C2-Symmetrical Thiodigalactoside Bis-Benzamido Derivatives as High-Affinity inhibitors of Galectin-3: Efficient lectin inhibition through double Arginine-Arene interactions. Angew. Chem. Int. Ed. Engl., 2005, 44(32), 5110-5112.
Tejler, J.; Tullberg, E.; Frejd, T.; Leffler, H.; Nilsson, U.J. Synthesis of multivalent lactose derivatives by 1,3-Dipolar cycloadditions: Selective Galectin-1 inhibition. Carbohydr. Res., 2006, 341(10), 1353-1362.
Rabinovich, G.A.; Cumashi, A.; Bianco, G.A.; Ciavardelli, D.; Iurisci, I.; D’Egidio, M.; Piccolo, E.; Tinari, N.; Nifantiev, N.; Iacobelli, S. Synthetic Lactulose Amines: Novel class of anticancer agents that induce tumor-cell apoptosis and inhibit Galectin-Mediated homotypic cell aggregation and endothelial cell morphogenesis. Glycobiology, 2006, 16(3), 210-220.
Giguère, D.; Bonin, M-A.; Cloutier, P.; Patnam, R.; St-Pierre, C.; Sato, S.; Roy, R. Synthesis of stable and selective inhibitors of human Galectins-1 and -3. Bioorg. Med. Chem., 2008, 16, 7811-7823.
Giguère, D.; Sato, S.; St-Pierre, C.; Sirois, S.; Roy, R. Aryl O- and S-Galactosides and lactosides as specific inhibitors of human galectins-1 and -3: Role of electrostatic potential at O-3. Bioorg. Med. Chem. Lett., 2006, 16(16), 1668-1672.
Peterson, K.; Kumar, R.; Stenström, O.; Verma, P.; Verma, P.R.; Håkansson, M.; Kahl-Knutsson, B.; Zetterberg, F.; Leffler, H.; Akke, M.; Logan, D.T.; Nilsson, U.J. Systematic tuning of fluoro-galectin-3 interactions provides thiodigalactoside derivatives with single-digit Nm affinity and high Selectivity. J. Med. Chem., 2018, 61(3), 1164-1175.
Rajput, V.K.; Leffler, H.; Nilsson, U.J.; Mukhopadhyay, B. Synthesis and evaluation of iminocoumaryl and coumaryl derivatized glycosides as galectin Antagonists. Bioorg. Med. Chem. Lett., 2014, 24(15), 3516-3520.
Tejler, J.; Salameh, B.; Leffler, H.; Nilsson, U.J. Fragment-Based development of Triazole-Substituted O-Galactosyl Aldoximes with Fragment-Induced affinity and selectivity for Galectin-3. Org. Biomol. Chem., 2009, 7(19), 3982.
van Hattum, H.; Branderhorst, H.M.; Moret, E.E.; Nilsson, U.J.; Leffler, H.; Pieters, R.J. Tuning the preference of thiodigalactoside- and Lactosamine-Based ligands to Galectin-3 over Galectin-1. J. Med. Chem., 2013, 56(3), 1350-1354.
Giguère, D.; Patnam, R.; Bellefleur, M-A.; St-Pierre, C.; Sato, S.; Roy, R. Carbohydrate triazoles and isoxazoles as inhibitors of Galectins-1 and -3. Chem. Commun., 2006, 22(1), 2379-2381.
Pandey, R.K.; Dougherty, T.J. Galectin recognized photosensitizers for photodynamic therapy, U. S. Patent, US6849607B2 2005.
André, S.; Giguère, D.; Dam, T.K.; Brewer, F.; Gabius, H-J.; Roy, R. Synthesis and screening of a small glycomimetic library for inhibitory activity on medically relevant Galactoside-Specific lectins in assays of increasing Biorelevance. New J. Chem., 2010, 34(10), 2229.
Cumpstey, I.; Salomonsson, E.; Sundin, A.; Leffler, H.; Nilsson, U.J. Double Affinity Amplification of Galectin-Ligand Interactions through Arginine-Arene Interactions: Synthetic, thermodynamic, and computational studies with aromatic diamido Thiodigalactosides. Chemistry, 2008, 14(14), 4233-4245.
Cumpstey, I.; Salomonsson, E.; Sundin, A.; Leffler, H.; Nilsson, U.J. Studies of Arginine-Arene interactions through synthesis and evaluation of a series of Galectin-Binding aromatic lactose esters. ChemBioChem, 2007, 8(12), 1389-1398.
Juers, D.H.; Matthews, B.W.; Huber, R.E. LacZ β-Galactosidase: Structure and function of an enzyme of historical and molecular biological importance. Protein Sci., 2012, 21(1), 1792-1807.
Huflejt, M.; Mossine, V.; Croft, M. Galectins -1 and -4 in tumor development. US20030109464A1 2003.
Vrasidas, I.; André, S.; Valentini, P.; Böck, C.; Lensch, M.; Kaltner, H.; Liskamp, R.M.J.; Gabius, H-J.; Pieters, R.J. Rigidified multivalent lactose molecules and their interactions with mammalian Galectins: A route to selective inhibitors. Org. Biomol. Chem., 2003, 1(5), 803-810.
Tejler, J.; Tullberg, E.; Frejd, T.; Leffler, H.; Nilsson, U.J. Synthesis of Multivalent Lactose Derivatives by 1,3-Dipolar Cycloadditions: Selective Galectin-1 inhibition. Carbohydr. Res., 2006, 341(10), 1353-1362.
Klyosov, A.; Zomer, E.; Platt, D. DAVANAT ® (GM-CT-01) and Colon Cancer: Preclinical and clinical (Phase I and II) Studies. In: Glycobiology and Drug Design; Klyosov, A.A., Ed.; American Chemical Society: Washington, DC, 2012; Vol. 1102, pp. 89-130.
Liu, Q.; Sacco, P.; Marsich, E.; Furlani, F.; Arib, C.; Djaker, N.; Lamy de la Chapelle, M.; Donati, I.; Spadavecchia, J. Lactose-modified chitosan Gold(III)-PEGylated Complex-Bioconjugates: From synthesis to interaction with targeted Galectin-1 protein. Bioconjug. Chem., 2018, 29(10), 3352-3361.
Dings, R.P.M.; Arroyo, M.M.; Lockwood, N.A.; van Eijk, L.I.; Haseman, J.R.; Griffioen, A.W.; Mayo, K.H. Beta-Sheet is the bioactive conformation of the anti-angiogenic anginex peptide. Biochem. J., 2003, 373(1), 281-288.
Mayo, K.H.; Dings, R.P.M.; Flader, C.; Nesmelova, I.; Hargittai, B.; van der Schaft, D.W.J.; van Eijk, L.I.; Walek, D.; Haseman, J.; Hoye, T.R.; Griffioen, A.W. Design of a partial peptide mimetic of anginex with antiangiogenic and anticancer activity. J. Biol. Chem., 2003, 278(1), 45746-45752.
Dings, R.P.M.; Kumar, N.; Miller, M.C.; Loren, M.; Rangwala, H.; Hoye, T.R.; Mayo, K.H. Structure-Based optimization of angiostatic agent 6DBF7, an allosteric antagonist of Galectin-1. J. Pharmacol. Exp. Ther., 2013, 344(3), 589-599.
Dings, R.P.M.; Van Laar, E.S.; Webber, J.; Zhang, Y.; Griffin, R.J.; Waters, S.J.; MacDonald, J.R.; Mayo, K.H. Ovarian tumor growth regression using a combination of vascular targeting agents anginex or topomimetic 0118 and the chemotherapeutic Irofulven. Cancer Lett., 2008, 265(2), 270-280.
Zucchetti, M.; Bonezzi, K.; Frapolli, R.; Sala, F.; Borsotti, P.; Zangarini, M.; Cvitkovic, E.; Noel, K.; Ubezio, P.; Giavazzi, R.; D’Incalci, M.; Taraboletti, G. Pharmacokinetics and antineoplastic activity of Galectin-1-Targeting OTX008 in combination with sunitinib. Cancer Chemother. Pharmacol., 2013, 72(4), 879-887.
Rabinovich, G.; Castagna, L.; Landa, C.; Riera, C.M.; Sotomayor, C. Regulated expression of a 16-Kd Galectin-like protein in Activated rat macrophages. J. Leukoc. Biol., 1996, 59(3), 363-370.
St-Pierre, C.; Ouellet, M.; Tremblay, M.J.; Sato, S. Galectin-1 and HIV-1 infection. Methods Enzymol., 2010, 480(1), 267-294.
St-Pierre, C.; Ouellet, M.; Giguère, D.; Ohtake, R.; Roy, R.; Sato, S.; Tremblay, M.J. Galectin-1-Specific inhibitors as a new class of compounds to treat HIV-1 infection. Antimicrob. Agents Chemother., 2012, 56(1), 154-162.
Aalinkeel, R.; Mangum, C.S.; Abou-Jaoude, E.; Reynolds, J.L.; Liu, M.; Sundquist, K.; Parikh, N.U.; Chaves, L.D.; Mammen, M.J.; Schwartz, S.A.; Mahajan, S.D. Galectin-1 reduces neuroinflammation via modulation of nitric Oxide-Arginase signaling in hiv-1 transfected microglia: A gold Nanoparticle-Galectin-1 “Nanoplex” a possible neurotherapeutic? J. Neuroimmune Pharmacol., 2017, 12(1), 133-151.
Chatterjee, A.; Ratner, D.M.; Ryan, C.M.; Johnson, P.J.; O’Keefe, B.R.; Secor, W.E.; Anderson, D.J.; Robbins, P.W.; Samuelson, J. Anti-Retroviral lectins have modest effects on adherence of trichomonas vaginalis to epithelial cells in vitro and on recovery of tritrichomonas foetus in a mouse vaginal model. PLOS One, 2015, 10(2)e0135340

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 24 September, 2019
Page: [1369 - 1378]
Pages: 10
DOI: 10.2174/1389557519666190304120821
Price: $65

Article Metrics

PDF: 59