Pharmaceutical Research

, 36:176 | Cite as

A Sialylated-Bortezomib Prodrug Strategy Based on a Highly Expressed Selectin Target for the Treatment of Leukemia or Solid Tumors

  • Mingqi Liu
  • Xueying Tang
  • Junqiang Ding
  • Mengyang Liu
  • Bowen Zhao
  • Yihui Deng
  • Yanzhi SongEmail author
Research Paper



This study aimed to explore the potential of sialic acid - related selectin targeting strategy in the treatment of leukemia and some solid tumors. We expected it could “actively” bind tumor cells and kill them, reducing non-specific toxicity to normal cells.


BOR-SA prodrug was synthesized by reacting an ortho-dihydroxy group in SA with a boronic acid group in BOR. Two kinds of leukemia cells (RAW264.7 and HL60 cells), one solid sarcoma cell model (S180 cells) and their corresponding normal cells (monocytes (MO), neutrophil (NE) and fibroblast (L929)) were selected for the in vitro cell experiments (cytotoxicity, cellular uptake, cell cycle and apoptosis experiments). The S180 tumor-bearing Kunming mice model was established for anti-tumor pharmacodynamic experiments.


In vitro cell assay results showed that uptake of BOR-SA by HL60 and S180 cells were increased compared with the control group. BOR-SA induced a lower IC50, higher ratio of apoptosis and cell cycle arrest of tumor cells. In vivo anti-S180 tumor pharmacodynamics experiments showed that mice in the BOR-SA group had higher tumor inhibition rate, higher body weight and lower immune organ toxicity compared with the control group.


sialic acid-mediated selectin targeting strategy may have great potential in the treatment of related tumors.


Bortezomib leukemia selectin-targeting sialic acid tumor-targeted 



Annexin V-FITC






Bortezomib solution


Bortezomib-sialic acid


Cell Counting Kit-8


Fetal bovine serum














PE-conjugated CD115 antibody


PE-conjugated Ly-6G/Ly-6C antibody


Relative Tumor-inhibition index


Sialic acid




Tumor-inhibition index


Tumor volume inhibition rate (volume)


Compliance with Ethical Standards

Conflict of Interest

There are no conflicts of interest to declare.

Supplementary material

11095_2019_2714_MOESM1_ESM.docx (301 kb)
ESM 1 (DOCX 301 kb)


  1. 1.
    Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501(7467):328.CrossRefGoogle Scholar
  2. 2.
    Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005;5(4):311.CrossRefGoogle Scholar
  3. 3.
    Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001;98(8):2301–7.CrossRefGoogle Scholar
  4. 4.
    Horton TM, Gannavarapu A, Blaney SM, D’Argenio DZ, Plon SE, Berg SL. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother Pharmacol. 2006;58(1):13–23.CrossRefGoogle Scholar
  5. 5.
    Paramore A, Frantz S. Bortezomib. In: Nature Publishing Group; 2003.Google Scholar
  6. 6.
    Blum W, Schwind S, Tarighat SS, Geyer S, Eisfeld A-K, Whitman S, et al. Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia. Blood. 2012. Scholar
  7. 7.
    Marinaro WA, Schieber LJ, Munson EJ, Day VW, Stella VJ. Properties of a model aryl boronic acid and its boroxine. J Pharm Sci. 2012;101(9):3190–8.CrossRefGoogle Scholar
  8. 8.
    Sallusto F, Cella M, Danieli C, Lanzavecchia A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med. 1995;182(2):389–400.CrossRefGoogle Scholar
  9. 9.
    McKenzie EJ, Taylor PR, Stillion RJ, Lucas AD, Harris J, Gordon S, et al. Mannose receptor expression and function define a new population of murine dendritic cells. J Immunol. 2007;178(8):4975–83.CrossRefGoogle Scholar
  10. 10.
    Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, et al. Non-proteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011. Scholar
  11. 11.
    Richardson PG, Mitsiades C, Hideshima T, Anderson KC. Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med. 2006;57:33–47.CrossRefGoogle Scholar
  12. 12.
    Yoshizawa K, Mukai HY, Miyazawa M, Miyao M, Ogawa Y, Ohyashiki K, et al. Bortezomib therapy-related lung disease in J apanese patients with multiple myeloma: incidence, mortality and clinical characterization. Cancer Sci. 2014;105(2):195–201.CrossRefGoogle Scholar
  13. 13.
    Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, et al. Bortezomib induction, reduced-intensity transplantation and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013. Scholar
  14. 14.
    Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 2004;22(11):2108–21.CrossRefGoogle Scholar
  15. 15.
    Wiederschain GY. Essentials of glycobiology. Biochem Mosc. 2009;74(9):1056–6.CrossRefGoogle Scholar
  16. 16.
    Schauer R. Sialic acids: fascinating sugars in higher animals and man. Zoology. 2004;107(1):49–64.CrossRefGoogle Scholar
  17. 17.
    RodrÍguez E, Schetters ST, van Kooyk Y. The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat Rev Immunol. 2018;18(3):204.CrossRefGoogle Scholar
  18. 18.
    Matsumoto A, Cabral H, Sato N, Kataoka K, Miyahara Y. Assessment of tumor metastasis by the direct determination of cell-membrane sialic acid expression. Angew Chem. 2010;122(32):5626–9.CrossRefGoogle Scholar
  19. 19.
    Büll C, Heise T, Adema GJ, Boltje TJ. Sialic acid mimetics to target the sialic acid–Siglec axis. Trends Biochem Sci. 2016;41(6):519–31.CrossRefGoogle Scholar
  20. 20.
    Borsig L, Wong R, Hynes RO, Varki NM, Varki A. Synergistic effects of L-and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci. 2002;99(4):2193–8.CrossRefGoogle Scholar
  21. 21.
    Witz IP. The selectin–selectin ligand axis in tumor progression. Cancer Metastasis Rev. 2008;27(1):19–30.CrossRefGoogle Scholar
  22. 22.
    Zhang L, Luo G, Yuan H, Wei G. Soluble P-selectin and L-selectin levels in serum of colorectal cancer patients and its clinical significance. China Oncology. 2014;8:599–603.Google Scholar
  23. 23.
    Burgess M, Gill DS, Singhania R, Cheung C, Chambers L, Reynolds BA, et al. CD62L as a therapeutic target in chronic lymphocytic leukemia. Clin Cancer Res. 2013. Scholar
  24. 24.
    Qian F, Hanahan D, Weissman IL. L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis. Proc Natl Acad Sci. 2001;98(7):3976–81.CrossRefGoogle Scholar
  25. 25.
    Luo C, Huang B, Huang Q, Chen J, Haishan L, Wei Y, et al. Expression and clinical significance of P-selectin in colorectal cancer cells. Tianjin Medical Journal. 2016;44(5):540–2.Google Scholar
  26. 26.
    Luo X, Liu M, Hu L, Qiu Q, Liu X, Li C, et al. Targeted delivery of pixantrone to neutrophils by poly (sialic acid)-p-octadecylamine conjugate modified liposomes with improved antitumor activity. Int J Pharm. 2018;547:315–29.CrossRefGoogle Scholar
  27. 27.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.CrossRefGoogle Scholar
  28. 28.
    Liu M, Luo X, Qiu Q, Kang L, Li T, Ding J, et al. Redox-and pH-sensitive glycan (Polysialic acid) derivatives and F127 mixed micelles for tumor-targeted drug delivery. Mol Pharm. 2018;15(12):5534–45.CrossRefGoogle Scholar
  29. 29.
    Wickström M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sjöberg P, et al. Melflufen-a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8(39):66641.CrossRefGoogle Scholar
  30. 30.
    Jin Y, Wu Z, Li C, Zhou W, Shaw JP, Baguley BC, et al. Optimization of weight ratio for DSPE-PEG/TPGS hybrid micelles to improve drug retention and tumor penetration. Pharm Res. 2018;35(1):13.CrossRefGoogle Scholar
  31. 31.
    Jayant S, Khandare JJ, Wang Y, Singh AP, Vorsa N, Minko T. Targeted sialic acid–doxorubicin prodrugs for intracellular delivery and cancer treatment. Pharm Res. 2007;24(11):2120–30.CrossRefGoogle Scholar
  32. 32.
    Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337–41.CrossRefGoogle Scholar
  33. 33.
    Mo R, Sun Q, Li N, Zhang C. Intracellular delivery and antitumor effects of pH-sensitive liposomes based on zwitterionic oligopeptide lipids. Biomaterials. 2013;34(11):2773–86.CrossRefGoogle Scholar
  34. 34.
    Armstrong MB, Schumacher KR, Mody R, Yanik GA, Pipari AW, Castle VP. Bortezomib as a therapeutic candidate for neuroblastoma. Journal of experimental therapeutics & oncology. 2008;7(2):135–45.Google Scholar
  35. 35.
    Albero MP, Vaquer JM, Andreu EJ, Villanueva JJ, Franch L, Ivorra C, et al. Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and-resistant Bcr-Abl1-expressing cells. Oncogene. 2010;29(22):3276.CrossRefGoogle Scholar
  36. 36.
    Tarnowski GS, Mountain IM, Stock CC. Influence of genotype of host on regression of solid and ascitic forms of sarcoma 180 and effect of chemotherapy on the solid form. Cancer Res. 1973;33(8):1885–8.PubMedGoogle Scholar
  37. 37.
    Alfaro G, Lomeli C, Ocadiz R, Ortega V, Barrera R, Ramirez M, et al. Immunologic and genetic characterization of S180, a cell line of murine origin capable of growing in different inbred strains of mice. Vet Immunol Immunopathol. 1992;30(4):385–98.CrossRefGoogle Scholar
  38. 38.
    Schiffer L, Nelson JS, Dilettuso B, Migliorato D, Randolph W. Cytokinetics of the S-180 ascites tumor system. Cell Prolif. 1973;6(2):165–72.CrossRefGoogle Scholar
  39. 39.
    Xiao J-H, Zhang Y, Liang G-Y, Liu R-M, Li X-G, Zhang L-T, et al. Synergistic antitumor efficacy of antibacterial helvolic acid from Cordyceps taii and cyclophosphamide in a tumor mouse model. Exp Biol Med. 2017;242(2):214–22.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mingqi Liu
    • 1
  • Xueying Tang
    • 1
  • Junqiang Ding
    • 1
  • Mengyang Liu
    • 1
  • Bowen Zhao
    • 1
  • Yihui Deng
    • 1
  • Yanzhi Song
    • 1
    Email author
  1. 1.College of PharmacyShenyang Pharmaceutical UniversityBenxiChina

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