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Investigational New Drugs

, Volume 36, Issue 2, pp 323–331 | Cite as

Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas

  • Franciele Cristina Kipper
  • Andrew Oliveira Silva
  • André Luis Marc
  • Gláucia Confortin
  • Augusto Valadão Junqueira
  • Eliseu Paglioli Neto
  • Guido Lenz
SHORT REPORT

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.

Keywords

Glioblastoma Temozolomide Vinblastine Mebendazole Long-term analysis 

Notes

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).

Compliance with ethical standards

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.

Supplementary material

10637_2017_503_MOESM1_ESM.docx (17 kb)
Sup Table 1 (DOCX 16.9 kb)
10637_2017_503_Fig4_ESM.gif (256 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)

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High Resolution Image (EPS 2.05 mb)
10637_2017_503_Fig5_ESM.gif (198 kb)
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)

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High Resolution Image (EPS 1.40 mb)
10637_2017_503_Fig6_ESM.gif (102 kb)
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)

10637_2017_503_MOESM4_ESM.eps (1.5 mb)
High Resolution Image (EPS 1.49 mb)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Franciele Cristina Kipper
    • 1
    • 2
  • Andrew Oliveira Silva
    • 1
    • 2
  • André Luis Marc
    • 3
  • Gláucia Confortin
    • 3
  • Augusto Valadão Junqueira
    • 3
  • Eliseu Paglioli Neto
    • 3
  • Guido Lenz
    • 1
    • 2
    • 4
  1. 1.Department of BiophysicsFederal University of Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  2. 2.Center of BiotechnologyFederal University of Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  3. 3.Department of Neurosurgery, São Lucas HospitalPontifical Catholic University of Rio Grande do Sul (PUCRS)Porto AlegreBrazil
  4. 4.Departamento de Biofísica, Instituto de BiociênciasUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil

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