Skip to main content

Advertisement

SpringerLink
Log in

Anti-glioma Activity of Dapsone and Its Enhancement by Synthetic Chemical Modification

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The sulfone dapsone is an old antibiotic used for the treatment of mycobacterial and protozoal infections. We postulated before that dapsone might possess biological activity exceeding its anti-infectious properties and that it could potentially be repurposed for the treatment of glioma. To test this hypothesis, we treated established and primary cultured glioma cells with dapsone or several dapsone analogues which we previously synthesized (D2–D5) and determined effects on proliferation, anchorage-independent growth and migration. While dapsone and its synthetic analogues D2–D5 displayed only modest anti-proliferative activity, important neoplastic features such as anchorage-independent growth, clonogenic survival and directed migration were significantly inhibited by dapsone treatment. Moreover, dapsone analogues D3, D4 and D5 yielded even enhanced anti-glioma activity against different pro-neoplastic features. Overall these data suggest that dapsone provides activity against glioma which can be further enhanced by molecular modifications. These compounds could potentially serve as a therapeutic adjunct to the treatment of gliomas in a repurposing approach.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Wozel G, Barth J (1988) Current aspects of modes of action of dapsone. Int J Dermatol 27:547–552

    Article  CAS  PubMed  Google Scholar 

  2. Pfeiffer C, Wozel G (2003) Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol 48:308–309

    Article  PubMed  Google Scholar 

  3. Wozel G, Blasum C (2014) Dapsone in dermatology and beyond. Arch Dermatol Res 306:103–124

    Article  CAS  PubMed  Google Scholar 

  4. Boccellino M, Quagliuolo L, Alaia C, Grimaldi A, Addeo R, Nicoletti GF, Kast RE, Caraglia M (2016) The strange connection between epidermal growth factor receptor tyrosine kinase inhibitors and dapsone: from rash mitigation to the increase in anti-tumor activity. Curr Med Res Opin 32:1–10

    Article  Google Scholar 

  5. Hill QA (2015) How does dapsone work in immune thrombocytopenia? Implications for dosing. Blood 125:3666–3668

    Article  CAS  PubMed  Google Scholar 

  6. Chang DJ, Lamothe M, Stevens RM, Sigal LH (1996) Dapsone in rheumatoid arthritis. Semin Arthritis Rheum 25:390–403

    Article  CAS  PubMed  Google Scholar 

  7. Haar D, Solvkjaer M, Unger B, Rasmussen KJ, Christensen L, Hansen TM (1993) A double-blind comparative study of hydroxychloroquine and dapsone, alone and in combination, in rheumatoid arthritis. Scand J Rheumatol 22:113–118

    Article  CAS  PubMed  Google Scholar 

  8. Kast RE (2015) Erlotinib augmentation with dapsone for rash mitigation and increased anti-cancer effectiveness. SpringerPlus 4:638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kast RE, Boockvar JA, Bruning A, Cappello F, Chang WW, Cvek B, Dou QP, Duenas-Gonzalez A, Efferth T, Focosi D, Ghaffari SH, Karpel-Massler G, Ketola K, Khoshnevisan A, Keizman D, Magne N, Marosi C, McDonald K, Munoz M, Paranjpe A, Pourgholami MH, Sardi I, Sella A, Srivenugopal KS, Tuccori M, Wang W, Wirtz CR, Halatsch ME (2013) A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget 4:502–530

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kast RE, Lefranc F, Karpel-Massler G, Halatsch ME (2012) Why dapsone stops seizures and may stop neutrophils’ delivery of VEGF to glioblastoma. Br J Neurosurg 26:813–817

    Article  CAS  PubMed  Google Scholar 

  11. Chen XY, Buschmann H, Bolm C (2012) Sulfoximine- and sulfilimine-based dapson analogues; syntheses and bioactivities. Synlett 23:2808–2810

    Article  CAS  Google Scholar 

  12. Karpel-Massler G, Horst BA, Shu C, Chau L, Tsujiuchi T, Bruce JN, Canoll P, Greene LA, Angelastro JM, Siegelin MD (2016) A synthetic cell-penetrating dominant-negative ATF5 peptide exerts anticancer activity against a broad spectrum of treatment-resistant cancers. Clin Cancer Res 22:4698–4711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Karpel-Massler G, Westhoff MA, Zhou S, Nonnenmacher L, Dwucet A, Kast RE, Bachem MG, Wirtz CR, Debatin KM, Halatsch ME (2013) Combined inhibition of HER1/EGFR and RAC1 results in a synergistic antiproliferative effect on established and primary cultured human glioblastoma cells. Mol Cancer Ther 12:1783–1795

    Article  CAS  PubMed  Google Scholar 

  14. Schneider M, Strobele S, Nonnenmacher L, Siegelin MD, Tepper M, Stroh S, Hasslacher S, Enzenmuller S, Strauss G, Baumann B, Karpel-Massler G, Westhoff MA, Debatin KM, Halatsch ME (2016) A paired comparison between glioblastoma “stem cells” and differentiated cells. Int J Cancer 138:1709–1718

    Article  CAS  PubMed  Google Scholar 

  15. Karpel-Massler G, Westhoff MA, Kast RE, Dwucet A, Nonnenmacher L, Wirtz CR, Debatin KM, Halatsch ME (2014) Artesunate enhances the antiproliferative effect of temozolomide on U87MG and A172 glioblastoma cell lines. Anticancer Agents Med Chem 14:313–318

    Article  CAS  PubMed  Google Scholar 

  16. Karpel-Massler G, Ramani D, Shu C, Halatsch ME, Westhoff MA, Bruce JN, Canoll P, Siegelin MD (2016) Metabolic reprogramming of glioblastoma cells by l-asparaginase sensitizes for apoptosis in vitro and in vivo. Oncotarget 7:33512–33528

    Article  PubMed  PubMed Central  Google Scholar 

  17. Karpel-Massler G, Ba M, Shu C, Halatsch ME, Westhoff MA, Bruce JN, Canoll P, Siegelin MD (2015) TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo. Oncotarget 6:36456–36471

    Article  PubMed  PubMed Central  Google Scholar 

  18. Karpel-Massler G, Kast RE, Westhoff MA, Dwucet A, Welscher N, Nonnenmacher L, Hlavac M, Siegelin MD, Wirtz CR, Debatin KM, Halatsch ME (2015) Olanzapine inhibits proliferation, migration and anchorage-independent growth in human glioblastoma cell lines and enhances temozolomide’s antiproliferative effect. J Neurooncol 122:21–33

    Article  CAS  PubMed  Google Scholar 

  19. Karpel-Massler G, Pareja F, Aime P, Shu C, Chau L, Westhoff MA, Halatsch ME, Crary JF, Canoll P, Siegelin MD (2014) PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. PLoS ONE 9:e114583

    Article  PubMed  PubMed Central  Google Scholar 

  20. Boer JC, van Marion DM, Joseph JV, Kliphuis NM, Timmer-Bosscha H, van Strijp JA, de Vries EG, den Dunnen WF, Kruyt FA, Walenkamp AM (2015) Microenvironment involved in FPR1 expression by human glioblastomas. J Neurooncol 123:53–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang J, Chen K, Chen J, Gong W, Dunlop NM, Howard OM, Gao Y, Bian XW, Wang JM (2010) The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells. Br J Cancer 102:1052–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhou Y, Bian X, Le Y, Gong W, Hu J, Zhang X, Wang L, Iribarren P, Salcedo R, Howard OZ, Farrar W, Wang JM (2005) Formylpeptide receptor FPR and the rapid growth of malignant human gliomas. J Natl Cancer Inst 97:823–835

    Article  CAS  PubMed  Google Scholar 

  23. Xu CP, Zhang HR, Chen FL, Yao XH, Liang ZQ, Zhang R, Cui Y, Qian C, Bian XW (2010) Human malignant glioma cells expressing functional formylpeptide receptor recruit endothelial progenitor cells for neovascularization. Int Immunopharmacol 10:1602–1607

    Article  CAS  PubMed  Google Scholar 

  24. Anderson R (1985) Enhancement by clofazimine and inhibition by dapsone of production of prostaglandin E2 by human polymorphonuclear leukocytes in vitro. Antimicrob Agents Chemother 27:257–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Harvath L, Yancey KB, Katz SI (1986) Selective inhibition of human neutrophil chemotaxis to N-formyl-methionyl-leucyl-phenylalanine by sulfones. J Immunol 137:1305–1311

    CAS  PubMed  Google Scholar 

  26. Chen JH, Yao XH, Gong W, Hu J, Zhou XD, Chen K, Liu H, Ping YF, Wang JM, Bian XW (2007) A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors. J Neurooncol 84:223–231

    Article  CAS  PubMed  Google Scholar 

  27. Chen JH, Bian XW, Yao XH, Gong W, Hu J, Chen K, Iribarren P, Zhao W, Zhou XD (2006) Nordy, a synthetic lipoxygenase inhibitor, inhibits the expression of formylpeptide receptor and induces differentiation of malignant glioma cells. Biochem Biophys Res Commun 342:1368–1374

    Article  CAS  PubMed  Google Scholar 

  28. Chen Y, Chen L, Li JY, Mukaida N, Wang Q, Yang C, Yin WJ, Zeng XH, Jin W, Shao ZM (2011) ER beta and PEA3 co-activate IL-8 expression and promote the invasion of breast cancer cells. Cancer Biol Ther 11:497–511

    Article  CAS  PubMed  Google Scholar 

  29. Kuwada Y, Sasaki T, Morinaka K, Kitadai Y, Mukaida N, Chayama K (2003) Potential involvement of IL-8 and its receptors in the invasiveness of pancreatic cancer cells. Int J Oncol 22:765–771

    CAS  PubMed  Google Scholar 

  30. Maxwell PJ, Neisen J, Messenger J, Waugh DJ (2014) Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells. Oncotarget 5:4895–4908

    Article  PubMed  PubMed Central  Google Scholar 

  31. Rong Y, Durden DL, Van Meir EG, Brat DJ (2006) Pseudopalisading necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65:529–539

    Article  PubMed  Google Scholar 

  32. Zhang B, Shi L, Lu S, Sun X, Liu Y, Li H, Wang X, Zhao C, Zhang H, Wang Y (2015) Autocrine IL-8 promotes F-actin polymerization and mediate mesenchymal transition via ELMO1-NF-κB-Snail signaling in glioma. Cancer Biol Ther 16:898–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ahn SH, Park H, Ahn YH, Kim S, Cho MS, Kang JL, Choi YH (2016) Necrotic cells influence migration and invasion of glioblastoma via NF-κB/AP-1-mediated IL-8 regulation. Sci Rep 6:24552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Han S, Liu Y, Li Q, Li Z, Hou H, Wu A (2015) Pre-treatment neutrophil-to-lymphocyte ratio is associated with neutrophil and T-cell infiltration and predicts clinical outcome in patients with glioblastoma. BMC Cancer 15:617

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kast RE, Karpel-Massler G, Halatsch ME (2014) CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget 5:8052–8082

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wozel G, Blasum C, Winter C, Gerlach B (1997) Dapsone hydroxylamine inhibits the LTB4-induced chemotaxis of polymorphonuclear leukocytes into human skin: results of a pilot study. Inflamm Res 46:420–422

    Article  CAS  PubMed  Google Scholar 

  37. Wozel G, Lehmann B (1995) Dapsone inhibits the generation of 5-lipoxygenase products in human polymorphonuclear leukocytes. Skin Pharmacol 8:196–202

    Article  CAS  PubMed  Google Scholar 

  38. Lücking U (2013) Sulfoximines: a neglected opportunity in medicinal chemistry. Angew Chem Int Ed Engl 52:9399–9408

    Article  PubMed  Google Scholar 

  39. Frings M, Bolm C, Blum A, Gnamm C (2016) Sulfoximines from a Medicinal Chemist’s Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery. Eur J Med Chem 126:225–245

    Article  PubMed  Google Scholar 

  40. Park S, Baars H, Buschmann H, Baron JM, Amann PM, Czaja K, Hollert H, Bluhm K, Redelstein R, Bolm C (2013) N-cyano sulfoximines: COX inhibition, anti-cancer activity, cellular toxicity, and mutagenicity. ChemMedChem 8:217–220

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a scholarship from the Dr. Mildred Scheel foundation of the German Cancer Aid and a young investigator’s award of the University of Ulm to GKM. XYC is grateful to the Chinese Scholarship Council for predoctoral stipend No. 2010634128. We are grateful to Jens Reball for his work on D5.

Author information

Author notes

  1. Xiao Yun Chen

    Present address: The School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Mengxi Road No. 2, Zhenjiang, 212003, Jiangsu, China

Authors and Affiliations

  1. Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA

    Georg Karpel-Massler, Markus D. Siegelin & Elisabeth Schneider

  2. Department of Neurological Surgery, Ulm University Medical Center, Ulm, Germany

    Georg Karpel-Massler, Annika Dwucet, Christian Rainer Wirtz & Marc-Eric Halatsch

  3. IIAIGC Study Center, Burlington, VT, USA

    Richard E. Kast

  4. Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany

    Mike-Andrew Westhoff

  5. Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany

    Xiao Yun Chen & Carsten Bolm

Authors
  1. Georg Karpel-Massler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard E. Kast
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus D. Siegelin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annika Dwucet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elisabeth Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mike-Andrew Westhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Rainer Wirtz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiao Yun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marc-Eric Halatsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carsten Bolm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Georg Karpel-Massler.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karpel-Massler, G., Kast, R.E., Siegelin, M.D. et al. Anti-glioma Activity of Dapsone and Its Enhancement by Synthetic Chemical Modification. Neurochem Res 42, 3382–3389 (2017). https://doi.org/10.1007/s11064-017-2378-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-017-2378-6

Keywords

Search

Navigation