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Low Dose of Doxorubicin Potentiates the Effect of Temozolomide in Glioblastoma Cells

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Abstract

Glioblastoma (GBM) is an aggressive brain tumor with temozolomide (TMZ)-based chemotherapy as the main therapeutic strategy. Doxorubicin (DOX) is not used in gliomas due to its low bioavailability in the brain; however, new delivery strategies and low doses may be effective in the long term, especially as part of a drug cocktail. Our aim was to evaluate the chronic effects of low doses of DOX and TMZ in GBM. Human U87-ATCC cells and a primary GBM culture were chronically treated with TMZ (5 μM) and DOX (1 and 10 nM) alone or combined. DOX resulted in a reduction in the number of cells over a period of 35 days and delayed the cell regrowth. In addition, DOX induced cell senescence and reduced tumor sphere formation and the proportion of NANOG- and OCT4-positive cells after 7 days. Low doses of TMZ potentiated the effects of DOX on senescence and sphere formation. This combined response using low doses of DOX may pave the way for its use in glioma therapy, with new technologies to overcome its low blood–brain barrier permeability.

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Acknowledgements

This work was supported by CAPES Probitec 004/2012 and FAPERGS Pronem 11/2072-2. ESV and PLCL received CAPES fellowships and GL receives CNPq fellowship.

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Correspondence to Guido Lenz or Patrícia Luciana da Costa Lopez.

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The ethical committee at the UFRGS (n. 420.856) and PUCRS (n. 429.849) approved the use of LS12 cells.

Electronic Supplementary Material

Fig. S1

Flow cytometry analysis. (JPEG 72 kb)

High-resolution image. (EPS 1112 kb)

Fig. S2

Cumulative population doubling analysis of the primary GBM cell, LS12. (JPEG 252 kb)

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Fig. S3

Apoptosis and necrosis analysis after treatment with DOX and TMZ after 24 h. (JPEG 46 kb)

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Fig. S4

Nuclear morphometric analysis (NMA) after DOX 1 and 10 nM and TMZ 5 μM treatment. (JPEG 194 kb)

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Fig. S5

Number of spheres and protein quantification after 7 days of treatment. (JPEG 205 kb)

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Fig. S6

Radar graph was used in order to integrate all the results analysis using different combinations. (JPEG 262 kb)

High-resolution image. (EPS 2223 kb)

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Villodre, E.S., Kipper, F.C., Silva, A.O. et al. Low Dose of Doxorubicin Potentiates the Effect of Temozolomide in Glioblastoma Cells. Mol Neurobiol 55, 4185–4194 (2018). https://doi.org/10.1007/s12035-017-0611-6

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  • DOI: https://doi.org/10.1007/s12035-017-0611-6

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