Abstract
Glioblastoma is the most devastating primary brain tumor and effective therapies are not available. Treatment is based on surgery followed by radio and chemotherapy with temozolomide (TMZ), but TMZ increases patient survival only by 2 months. CD73, an enzyme responsible for adenosine production, emerges as a target for glioblastoma treatment. Indeed, adenosine causes tumor-promoting actions and CD73 inhibition increases sensitivity to TMZ in vitro. Here, a cationic nanoemulsion to nasal delivery of siRNA CD73 (NE-siRNA CD73) aiming glioblastoma treatment was employed alone or in combination with TMZ. In vitro, two glioblastoma cell lines (C6 and U138MG) with a chemo-resistant profile were used. Treatment alone with NE-siRNA CD73 reduced C6 and U138MG glioma cell viability by 70% and 25%, respectively. On the other hand, when NE-siRNA + TMZ combined treatment was employed, a reduction of 85% and 33% of cell viability was observed. Notably, treatment with NE-siRNA CD73 of glioma-bearing Wistar rats reduced tumor size by 80%, 60% more than the standard chemotherapy with TMZ, but no synergistic or additive effect was observed in vivo. Additionally, NE-siRNA CD73, TMZ or combined therapy decreased adenosine levels in liquor confirming the importance of this nucleoside on in vivo GB growth. Finally, no hemolytic potential was observed. These results suggest that nasal administration of NE-siRNA CD73 exhibits higher antiglioma effect when compared to TMZ. However, no synergistic or additive in vivo was promoted by the therapeutic regimen employed in this study.
References
Ostrom QT, Bauchet L, Davis FG et al (2014) The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol 16:896–913. https://doi.org/10.1093/neuonc/nou087
Chua J, Nafziger E, Leung D (2019) Evidence-based practice: temozolomide beyond glioblastoma. Curr Oncol Rep 21:1–9. https://doi.org/10.1007/s11912-019-0783-5
Stupp R, van den Bent MJ, Hegi ME (2005) Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep 5:198–206
Wijaya J, Fukuda Y, Schuetz JD (2017) Obstacles to brain tumor therapy: key ABC transporters. Int J Mol Sci. https://doi.org/10.3390/ijms18122544
Azambuja JH, Gelsleichter NE, Beckenkamp LR et al (2018) CD73 downregulation decreases In vitro and In vivo glioblastoma growth. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1240-4
Quezada C, Garrido W, Oyarzún C et al (2013) 5’-ectonucleotidase mediates multiple-drug resistance in glioblastoma multiforme cells. J Cell Physiol 228:602–608. https://doi.org/10.1002/jcp.24168
Bavaresco L, Bernardi A, Braganhol E et al (2008) The role of ecto-5′-nucleotidase/CD73 in glioma cell line proliferation. Mol Cell Biochem 319:61–68. https://doi.org/10.1007/s11010-008-9877-3
Azambuja JH, Schuh RS, Michels LR et al (2019) Nasal administration of cationic nanoemulsions as CD73-siRNA delivery system for glioblastoma treatment : a new therapeutical approach. Mol Neurobiol 57:635–649
Gehrcke M, Giuliani LM, Ferreira LM et al (2017) Enhanced photostability, radical scavenging and antitumor activity of indole-3-carbinol-loaded rose hip oil nanocapsules. Mater Sci Eng C. https://doi.org/10.1016/j.msec.2016.12.006
Da Silveira EF, Chassot JM, Teixeira FC et al (2013) Ketoprofen-loaded polymeric nanocapsules selectively inhibit cancer cell growth in vitro and in preclinical model of glioblastoma multiforme. Invest New Drugs 31:1424–1435. https://doi.org/10.1007/s10637-013-0016-y
da Silveira EF, Azambuja JH, de Carvalho TR et al (2017) Synthetic 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidin-4-ones exhibit selective in vitro antitumoral activity and inhibit cancer cell growth in a preclinical model of glioblastoma multiforme. Chem Biol Interact 266:1–9. https://doi.org/10.1016/j.cbi.2017.02.001
Torres A, Vargas Y, Uribe D et al (2016) Adenosine A 3 receptor elicits chemoresistance mediated by multiple resistance-associated protein-1 in human glioblastoma stem-like cells. Oncotarget 7:67373–67386. https://doi.org/10.18632/oncotarget.12033
Azambuja JH, Ludwig N, Braganhol E, Whiteside TL (2019) Inhibition of the adenosinergic pathway in cancer rejuvenates innate and adaptive immunity. Int J Mol Sci 20:5698. https://doi.org/10.3390/ijms20225698
Wink MR, Lenz G, Braganhol E et al (2003) Altered extracellular ATP, ADP and AMP catabolism in glioma cell lines. Cancer Lett 198:211–218. https://doi.org/10.1016/S0304-3835(03)00308-2
Funding
This study was supported by the Brazilian agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Processo 422298/2016-6; 310846/2014-5), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS-Processo 16/2551-0000265-7; PRONEX-Processo 16/2551-0000473-0); J.H. Azambuja, R.S. Schuh, N.E. Gelsleichter, L.R. Beckenkamp and G.S. Lenz were recipients of UFCSPA, CAPES or CNPq fellowships.
Author information
Authors and Affiliations
Contributions
Conceptualization: JHA; MAS; AMOB; HFT; EB. Methodology and investigation: JHA; RSS; LRM; LRB; GSL; NEG; FHO. Funding acquisition: HFT; EB. Writing-original draft: JHA. Writing-review and editing: EB; HFT; RSS; AMOB; MAS; MRW. Visualization: JHA; EB. Supervision: HFT, EB.
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare no conflicts of interest.
Ethical approval
All procedures used in the present study followed the Principles of Laboratory Animal Care from NIH and were approved by the Ethical Committee of Universidade Federal de Ciências da Saúde de Porto Alegre (protocol number 293/14).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
280_2020_4077_MOESM1_ESM.tif
Supplementary Fig. S1: Representative HE of implanted tumors demonstrating histopathological characteristics. The complete analysis is shown in Table S1. Images were taken at 200 × magnification. TMZ = Temozolomide; NE-siRNA CD73 = nanoemulsion-CD73 siRNA complex. (TIF 2644 kb)
Rights and permissions
About this article
Cite this article
Azambuja, J.H., Schuh, R.S., Michels, L.R. et al. CD73 as a target to improve temozolomide chemotherapy effect in glioblastoma preclinical model. Cancer Chemother Pharmacol 85, 1177–1182 (2020). https://doi.org/10.1007/s00280-020-04077-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-020-04077-1