Skip to main content

Advertisement

SpringerLink
Log in

Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas

  • SHORT REPORT
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Glioblastoma (GBM) is a very aggressive tumor that has not had substantial therapeutic improvement since the introduction of temozolomide (TMZ) in combination with radiotherapy. Combining TMZ with other chemotherapeutic agents is a strategy that could be further explored for GBM. To search for molecular predictors of TMZ resistance, the TCGA (The Cancer Genome Atlas) database was utilized to assess the impact of specific genes on TMZ response. Patients whose tumors expressed low levels of FGFR3 and AKT2 responded poorly to TMZ. Combination treatment of vinblastine (VBL) plus mebendazole (MBZ) with TMZ was more effective in reducing cell number in most cultures when compared to TMZ alone, especially in cells with low expression levels of FGFR3 and AKT2. Cell cycle distribution and nuclear morphometric analysis indicated that the triple combination of TMZ, VBL and MBZ (TVM) was able to induce polyploidy and senescence, in addition to increasing the Notch3 RNA level in patient-derived gliomas. Thus, this set of data suggests that the triple combination of TMZ, VBL and MBZ may be a considerable therapeutic alternative for the TMZ-tolerant gliomas that harbor low expression of FGFR3/AKT2.

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

Similar content being viewed by others

References

  1. Bai RY, Staedtke V, Riggins GJ (2011) Molecular targeting of glioblastoma: drug discovery and therapies. Trends Mol Med 17(6):301–312. https://doi.org/10.1016/j.molmed.2011.01.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kang JH, Adamson C (2015) Novel chemotherapeutics and other therapies for treating high-grade glioma. Expert Opin Investig Drugs 24(10):1361–1379. https://doi.org/10.1517/13543784.2015.1048332

    Article  CAS  PubMed  Google Scholar 

  3. Veliz I, Loo Y, Castillo O, Karachaliou N, Nigro O, Rosell R (2015) Advances and challenges in the molecular biology and treatment of glioblastoma-is there any hope for the future? Ann Transl Med 3(1):7. https://doi.org/10.3978/j.issn.2305-5839.2014.10.06

    PubMed  PubMed Central  Google Scholar 

  4. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10):987–996. https://doi.org/10.1056/NEJMoa043330

  5. Gutin PH, Wilson CB, Kumar AR, Boldrey EB, Levin V, Powell M, Enot KJ (1975) Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors. Cancer 35(5):1398–1404

    Article  CAS  PubMed  Google Scholar 

  6. Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD, Stelzer K, Brachman D, Suh JH, Schultz CJ, Bahary JP, Fisher BJ, Kim H, Murtha AD, Bell EH, Won M, Mehta MP, Curran WJ Jr (2016) Radiation plus Procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374(14):1344–1355. https://doi.org/10.1056/NEJMoa1500925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M (2013) Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 31(3):337–343. https://doi.org/10.1200/JCO.2012.43.2674

    Article  CAS  PubMed  Google Scholar 

  8. van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K (2013) Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31(3):344–350. https://doi.org/10.1200/JCO.2012.43.2229

    Article  PubMed  Google Scholar 

  9. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708. https://doi.org/10.1056/NEJMoa1308573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722. https://doi.org/10.1056/NEJMoa1308345

    Article  CAS  PubMed  Google Scholar 

  11. Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, Erridge S, Saran F, Gattamaneni R, Hopkins K, Beall S, Collins VP, Lee SM (2010) Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol 28(30):4601–4608. https://doi.org/10.1200/JCO.2009.27.1932

    Article  CAS  PubMed  Google Scholar 

  12. Medical Research Council Brain Tumor Working P (2001) Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol 19(2):509–518. https://doi.org/10.1200/JCO.2001.19.2.509

    Article  Google Scholar 

  13. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, https://doi.org/10.1200/JCO.2009.23.6497

  14. Chen Y, Xu R (2016) Drug repurposing for glioblastoma based on molecular subtypes. J Biomed Inform 64:131–138. https://doi.org/10.1016/j.jbi.2016.09.019

    Article  PubMed  Google Scholar 

  15. Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP (2014) Repurposing drugs in oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience 8:443. https://doi.org/10.3332/ecancer.2014.443

    Article  PubMed  PubMed Central  Google Scholar 

  16. Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, Pugh SL, Hegi M, Cloughesy T, Roth P, Reardon DA, Perry JR, Mehta MP, Stupp R, Weller M (2016) Does Valproic acid or Levetiracetam improve survival in glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J Clin Oncol 34(7):731–739. https://doi.org/10.1200/JCO.2015.63.6563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sato H, Senba H, Virgona N, Fukumoto K, Ishida T, Hagiwara H, Negishi E, Ueno K, Yamasaki H, Yano T (2007) Connexin 32 potentiates vinblastine-induced cytotoxicity in renal cell carcinoma cells. Mol Carcinog 46(3):215–224. https://doi.org/10.1002/mc.20267

    Article  CAS  PubMed  Google Scholar 

  18. Bouffet E, Jakacki R, Goldman S, Hargrave D, Hawkins C, Shroff M, Hukin J, Bartels U, Foreman N, Kellie S, Hilden J, Etzl M, Wilson B, Stephens D, Tabori U, Baruchel S (2012) Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol 30(12):1358–1363. https://doi.org/10.1200/JCO.2011.34.5843

    Article  CAS  PubMed  Google Scholar 

  19. Lee CT, Huang YW, Yang CH, Huang KS (2015) Drug delivery systems and combination therapy by using vinca alkaloids. Curr Top Med Chem 15(15):1491–1500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Stewart DJ, Lu K, Benjamin RS, Leavens ME, Luna M, Yap HY, Loo TL (1983) Concentration of vinblastine in human intracerebral tumor and other tissues. J Neuro-Oncol 1(2):139–144

    CAS  Google Scholar 

  21. Bai RY, Staedtke V, Aprhys CM, Gallia GL, Riggins GJ (2011) Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-Oncology 13(9):974–982. https://doi.org/10.1093/neuonc/nor077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Godoy PR, Mello SS, Magalhaes DA, Donaires FS, Nicolucci P, Donadi EA, Passos GA, Sakamoto-Hojo ET (2013) Ionizing radiation-induced gene expression changes in TP53 proficient and deficient glioblastoma cell lines. Mutat Res 756(1–2):46–55. https://doi.org/10.1016/j.mrgentox.2013.06.010

    Article  CAS  PubMed  Google Scholar 

  23. Brada M, Judson I, Beale P, Moore S, Reidenberg P, Statkevich P, Dugan M, Batra V, Cutler D (1999) Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 81(6):1022–1030. https://doi.org/10.1038/sj.bjc.6690802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Braithwaite PA, Roberts MS, Allan RJ, Watson TR (1982) Clinical pharmacokinetics of high dose mebendazole in patients treated for cystic hydatid disease. Eur J Clin Pharmacol 22(2):161–169

    Article  CAS  PubMed  Google Scholar 

  25. Silva AO, Felipe KB, Villodre ES, Lopez PL, Lenz G (2016) A guide for the analysis of long-term population growth in cancer. Tumour Biol 37(10):13743–13749. https://doi.org/10.1007/s13277-016-5255-z

    Article  PubMed  Google Scholar 

  26. Filippi-Chiela EC, Oliveira MM, Jurkovski B, Callegari-Jacques SM, da Silva VD, Lenz G (2012) Nuclear morphometric analysis (NMA): screening of senescence, apoptosis and nuclear irregularities. PLoS One 7(8):e42522. https://doi.org/10.1371/journal.pone.0042522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Silva AO, Dalsin E, Onzi GR, Filippi-Chiela EC, Lenz G (2016) The regrowth kinetic of the surviving population is independent of acute and chronic responses to temozolomide in glioblastoma cell lines. Exp Cell Res 348(2):177–183. https://doi.org/10.1016/j.yexcr.2016.09.014

    Article  CAS  PubMed  Google Scholar 

  28. Cui H, Kong Y, Xu M, Zhang H (2013) Notch3 functions as a tumor suppressor by controlling cellular senescence. Cancer Res 73(11):3451–3459. https://doi.org/10.1158/0008-5472.CAN-12-3902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Georgakilas AG, Martin OA, Bonner WM (2017) p21: a two-faced genome Guardian. Trends Mol Med 23(4):310–319. https://doi.org/10.1016/j.molmed.2017.02.001

    Article  CAS  PubMed  Google Scholar 

  30. Warren KE, Gururangan S, Geyer JR, McLendon RE, Poussaint TY, Wallace D, Balis FM, Berg SL, Packer RJ, Goldman S, Minturn JE, Pollack IF, Boyett JM, Kun LE (2012) A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a pediatric brain tumor consortium study. J Neuro-Oncol 106(3):643–649. https://doi.org/10.1007/s11060-011-0709-z

    Article  CAS  Google Scholar 

  31. Riganti C, Salaroglio IC, Caldera V, Campia I, Kopecka J, Mellai M, Annovazzi L, Bosia A, Ghigo D, Schiffer D (2013) Temozolomide downregulates P-glycoprotein expression in glioblastoma stem cells by interfering with the Wnt3a/glycogen synthase-3 kinase/beta-catenin pathway. Neuro-Oncology 15(11):1502–1517. https://doi.org/10.1093/neuonc/not104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Doudican N, Rodriguez A, Osman I, Orlow SJ (2008) Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol Cancer Res 6(8):1308–1315. https://doi.org/10.1158/1541-7786.MCR-07-2159

    Article  CAS  PubMed  Google Scholar 

  33. Doudican NA, Byron SA, Pollock PM, Orlow SJ (2013) XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts. Anti-Cancer Drugs 24(2):181–188. https://doi.org/10.1097/CAD.0b013e32835a43f1

    Article  CAS  PubMed  Google Scholar 

  34. Spagnuolo PA, Hu J, Hurren R, Wang X, Gronda M, Sukhai MA, Di Meo A, Boss J, Ashali I, Beheshti Zavareh R, Fine N, Simpson CD, Sharmeen S, Rottapel R, Schimmer AD (2010) The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood 115(23):4824–4833. https://doi.org/10.1182/blood-2009-09-243055

    Article  CAS  PubMed  Google Scholar 

  35. Moudi M, Go R, Yien CY, Nazre M (2013) Vinca alkaloids. Int J Prev Med 4(11):1231–1235

    PubMed  PubMed Central  Google Scholar 

  36. Boyle FM, Eller SL, Grossman SA (2004) Penetration of intra-arterially administered vincristine in experimental brain tumor. Neuro-Oncology 6(4):300–305. https://doi.org/10.1215/S1152851703000516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Althubiti M, Lezina L, Carrera S, Jukes-Jones R, Giblett SM, Antonov A, Barlev N, Saldanha GS, Pritchard CA, Cain K, Macip S (2014) Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis 5:e1528. https://doi.org/10.1038/cddis.2014.489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen CF, Dou XW, Liang YK, Lin HY, Bai JW, Zhang XX, Wei XL, Li YC, Zhang GJ (2016) Notch3 overexpression causes arrest of cell cycle progression by inducing Cdh1 expression in human breast cancer cells. Cell Cycle 15(3):432–440. https://doi.org/10.1080/15384101.2015.1127474

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Giovana R. Onzi for critical reading of the manuscript and Dr. Márcia Wink from Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) for making her laboratory available to perform some experiments.

Funding

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq (Universal 458,139/2014–9) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul - FAPERGS (PPSUS 1210–2551/13–1 and PRONEX 16/2551). FCK and GL are or were recipients of fellowships from CNPq, AOS is a recipient of a fellowship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior).

Author information

Author notes

  1. Franciele Cristina Kipper and Andrew Oliveira Silva contributed equally to this work.

Authors and Affiliations

  1. Department of Biophysics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, 91509-900, Brazil

    Franciele Cristina Kipper, Andrew Oliveira Silva & Guido Lenz

  2. Center of Biotechnology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, 91509-900, Brazil

    Franciele Cristina Kipper, Andrew Oliveira Silva & Guido Lenz

  3. Department of Neurosurgery, São Lucas Hospital, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

    André Luis Marc, Gláucia Confortin, Augusto Valadão Junqueira & Eliseu Paglioli Neto

  4. Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Av. Bento Gonçalves, 9500 Prédio 43431 Lab 115, Porto Alegre, RS, 91501-970, Brazil

    Guido Lenz

Authors
  1. Franciele Cristina Kipper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew Oliveira Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. André Luis Marc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gláucia Confortin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Augusto Valadão Junqueira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eliseu Paglioli Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guido Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guido Lenz.

Ethics declarations

Conflict of interest

The authors indicate no potential conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

All patients participated in clinical studies approved by the Federal University of Rio Grande do Sul and Pontifical Catholic University of Rio Grande do Sul Institutional Review Board. Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Sup Table 1

(DOCX 16.9 kb)

Sup Fig. 1

Overall survival of patients who received (TMZ+) or did not receive TMZ (TMZ-) according to the expression of the indicated genes from the TCGA databank on TMZ resistance. Numbers indicate the median OS for each group. (GIF 255 kb)

High Resolution Image (EPS 2.05 mb)

Sup Fig. 2

Acute and chronic sensitivity of GBM cell lines to TMZ, VBL or MBZ. A) Percentage of cells remaining 5 days after the beginning of the treatment in relation to control. B) Cumulative population doubling (CPD) profiles of GBM cells treated for 5 days with TMZ (50 μM), VBL (5 nM) and/or MBZ (500 nM). Symbols represent the day when the cells were counted and reseeded. (GIF 197 kb)

High Resolution Image (EPS 1.40 mb)

Sup Fig. 3

Expression of MSI1, MDR1, MERTK, PDGFRA and P2RX7 in patient-derived cultures and cell lines (normalized with RNA expression from adult cortex purchased from Agilent) was correlated with the % of cells after TVM treatment. (GIF 101 kb)

High Resolution Image (EPS 1.49 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kipper, F.C., Silva, A.O., Marc, A.L. et al. Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas. Invest New Drugs 36, 323–331 (2018). https://doi.org/10.1007/s10637-017-0503-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-017-0503-7

Keywords

Search

Navigation