Inhibition of Prostate Cancer Bone Metastasis by Synthetic TF Antigen Mimic/galectin-3 Inhibitor Lactulose-L-leucine

Overview

Journal Neoplasia

Publisher Elsevier

Specialty Oncology

Date 2012 Feb 23

PMID 22355275

Citations 40

Authors

Olga V Glinskii

Sudha Sud

Valeri V Mossine

Thomas P Mawhinney

Douglas C Anthony

Gennadi V Glinsky

Kenneth J Pienta

Vladislav V Glinsky

Affiliations

Soon will be listed here.

Abstract

Currently incurable, prostate cancer metastasis has a remarkable ability to spread to the skeleton. Previous studies demonstrated that interactions mediated by the cancer-associated Thomsen-Friedenreich glycoantigen (TF-Ag) and the carbohydrate-binding protein galectin-3 play an important role in several rate-limiting steps of cancer metastasis such as metastatic cell adhesion to bone marrow endothelium, homotypic tumor cell aggregation, and clonogenic survival and growth. This study investigated the ability of a synthetic small-molecular-weight nontoxic carbohydrate-based TF-Ag mimic lactulose-L-leucine (Lac-L-Leu) to inhibit these processes in vitro and, ultimately, prostate cancer bone metastasis in vivo. Using an in vivo mouse model, based on intracardiac injection of human PC-3 prostate carcinoma cells stably expressing luciferase, we investigated the ability of Lac-L-Leu to impede the establishment and growth of bone metastasis. Parallel-flow chamber assay, homotypic aggregation assay, modified Boyden chamber assay, and clonogenic growth assay were used to assess the effects of Lac-L-Leu on tumor cell adhesion to the endothelium, homotypic tumor cell aggregation, transendothelial migration, and clonogenic survival and growth, respectively. We report that daily intraperitoneal administration of Lac-L-Leu resulted in a three-fold (P < .05) decrease in metastatic tumor burden compared with the untreated control. Mechanistically, the effect of Lac-L-Leu, which binds and inhibits galectins by mimicking essential structural features of the TF-Ag, was associated with a dose-dependent inhibition of prostate cancer cell adhesion to bone marrow endothelium, homotypic aggregation, transendothelial migration, and clonogenic growth. We conclude that small-molecular-weight carbohydrate-based compounds targeting β-galactoside-mediated interactions could provide valuable means for controlling and preventing metastatic prostate cancer spread to the skeleton.

Citing Articles

Modified Citrus Pectin Treatment in Non-Metastatic Biochemically Relapsed Prostate Cancer: Long-Term Results of a Prospective Phase II Study.

Keizman D, Frenkel M, Peer A, Rosenbaum E, Sarid D, Leibovitch I Nutrients. 2023; 15(16).

PMID: 37630724 PMC: 10459199. DOI: 10.3390/nu15163533.

Poly(-vinylcaprolactam)-Gold Nanorods-5 Fluorouracil Hydrogels: In the Quest of a Material for Topical Therapies against Melanoma Skin Cancer.

Gonzalez-Ayon M, Rochin-Galaviz A, Zizumbo-Lopez A, Licea-Claverie A Pharmaceutics. 2023; 15(4).

PMID: 37111585 PMC: 10145490. DOI: 10.3390/pharmaceutics15041097.

Inhibition of galectins in cancer: Biological challenges for their clinical application.

Laderach D, Compagno D Front Immunol. 2023; 13:1104625.

PMID: 36703969 PMC: 9872792. DOI: 10.3389/fimmu.2022.1104625.

β-d-Galacto-pyranosyl-(1→4)-2-amino-2-de-oxy-α-d-gluco-pyran-ose hydro-chloride monohydrate (lactosamine).

Mossine V, Kelley S, Mawhinney T IUCrdata. 2022; 7(Pt 1):x220061.

PMID: 36337090 PMC: 9028551. DOI: 10.1107/S241431462200061X.

Isolipoic acid-linked gold nanoparticles bearing the thomsen friedenreich tumor-associated carbohydrate antigen: Stability and studies.

Mondal U, Barchi Jr J Front Chem. 2022; 10:1002146.

PMID: 36300019 PMC: 9588967. DOI: 10.3389/fchem.2022.1002146.

References

Fukumori T, Kanayama H, Raz A . The role of galectin-3 in cancer drug resistance. Drug Resist Updat. 2007; 10(3):101-8. PMC: 3626271. DOI: 10.1016/j.drup.2007.04.001. View

Tejler J, Skogman F, Leffler H, Nilsson U . Synthesis of galactose-mimicking 1H-(1,2,3-triazol-1-yl)-mannosides as selective galectin-3 and 9N inhibitors. Carbohydr Res. 2007; 342(12-13):1869-75. DOI: 10.1016/j.carres.2007.03.012. View

Kuwabara I, Liu F . Galectin-3 promotes adhesion of human neutrophils to laminin. J Immunol. 1996; 156(10):3939-44. View

Rubens R . Bone metastases--the clinical problem. Eur J Cancer. 1998; 34(2):210-3. DOI: 10.1016/s0959-8049(97)10128-9. View

Pienta K, Naik H, Akhtar A, Yamazaki K, Replogle T, Lehr J . Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst. 1995; 87(5):348-53. DOI: 10.1093/jnci/87.5.348. View

Johnson K, Glinskii O, Mossine V, Turk J, Mawhinney T, Anthony D . Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia. Neoplasia. 2007; 9(8):662-70. PMC: 1950436. DOI: 10.1593/neo.07433. View

Rabinovich G, Cumashi A, Bianco G, Ciavardelli D, Iurisci I, DEgidio M . 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. 2005; 16(3):210-20. DOI: 10.1093/glycob/cwj056. View

Glinsky V . Intravascular cell-to-cell adhesive interactions and bone metastasis. Cancer Metastasis Rev. 2006; 25(4):531-40. DOI: 10.1007/s10555-006-9029-8. View

Tantivejkul K, Kalikin L, Pienta K . Dynamic process of prostate cancer metastasis to bone. J Cell Biochem. 2004; 91(4):706-17. DOI: 10.1002/jcb.10664. View

10.

Siegel R, Ward E, Brawley O, Jemal A . Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011; 61(4):212-36. DOI: 10.3322/caac.20121. View

11.

Inohara H, Raz A . Effects of natural complex carbohydrate (citrus pectin) on murine melanoma cell properties related to galectin-3 functions. Glycoconj J. 1994; 11(6):527-32. DOI: 10.1007/BF00731303. View

12.

Heimburg J, Yan J, Morey S, Glinskii O, Huxley V, Wild L . Inhibition of spontaneous breast cancer metastasis by anti-Thomsen-Friedenreich antigen monoclonal antibody JAA-F11. Neoplasia. 2006; 8(11):939-48. PMC: 1716011. DOI: 10.1593/neo.06493. View

13.

Nangia-Makker P, Nakahara S, Hogan V, Raz A . Galectin-3 in apoptosis, a novel therapeutic target. J Bioenerg Biomembr. 2007; 39(1):79-84. PMC: 3616377. DOI: 10.1007/s10863-006-9063-9. View

14.

Roodman G . Mechanisms of bone metastasis. N Engl J Med. 2004; 350(16):1655-64. DOI: 10.1056/NEJMra030831. View

15.

Khaldoyanidi S, Glinsky V, Sikora L, Glinskii A, Mossine V, Quinn T . MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigen-galectin-3 interactions. J Biol Chem. 2002; 278(6):4127-34. DOI: 10.1074/jbc.M209590200. View

16.

Zou J, Glinsky V, Landon L, Matthews L, Deutscher S . Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion. Carcinogenesis. 2004; 26(2):309-18. DOI: 10.1093/carcin/bgh329. View

17.

Glinsky V, Glinsky G, Rittenhouse-Olson K, Huflejt M, Glinskii O, Deutscher S . The role of Thomsen-Friedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium. Cancer Res. 2001; 61(12):4851-7. View

18.

Glinsky G, Price J, Glinsky V, Mossine V, Kiriakova G, Metcalf J . Inhibition of human breast cancer metastasis in nude mice by synthetic glycoamines. Cancer Res. 1996; 56(23):5319-24. View

19.

Mehra R, Kumar-Sinha C, Shankar S, Lonigro R, Jing X, Philips N . Characterization of bone metastases from rapid autopsies of prostate cancer patients. Clin Cancer Res. 2011; 17(12):3924-32. PMC: 3117947. DOI: 10.1158/1078-0432.CCR-10-3120. View

20.

Fort S, Kim H, Hindsgaul O . Screening for galectin-3 inhibitors from synthetic lacto-N-biose libraries using microscale affinity chromatography coupled to mass spectrometry. J Org Chem. 2006; 71(19):7146-54. DOI: 10.1021/jo060485v. View