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Open Access Highly Accessed Research article

Pharmacological inhibition of poly(ADP-ribose) polymerase-1 modulates resistance of human glioblastoma stem cells to temozolomide

Lucio Tentori1*, Lucia Ricci-Vitiani2, Alessia Muzi1, Fabio Ciccarone35, Federica Pelacchi2, Roberta Calabrese35, Daniele Runci2, Roberto Pallini4, Paola Caiafa35 and Grazia Graziani1*

Author Affiliations

1 Department of System Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy

2 Department of Hematology, Oncology and Molecular Medicine, “Istituto Superiore di Sanità”, Viale Regina Elena 299, 00161 Rome, Italy

3 Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, “Sapienza” University of Rome, Viale Regina Elena 324, 00161 Rome, Italy

4 Institute of Neurosurgery, “Università Cattolica del Sacro Cuore”, Largo Agostino Gemelli 8, 00168 Rome, Italy

5 Pasteur Institute-“Fondazione Cenci Bolognetti”, Piazzale Aldo Moro 5, 00185 Rome, Italy

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BMC Cancer 2014, 14:151  doi:10.1186/1471-2407-14-151

Published: 5 March 2014

Abstract

Background

Chemoresistance of glioblastoma multiforme (GBM) has been attributed to the presence within the tumor of cancer stem cells (GSCs). The standard therapy for GBM consists of surgery followed by radiotherapy and the chemotherapeutic agent temozolomide (TMZ). However, TMZ efficacy is limited by O6-methylguanine-DNA-methyltransferase (MGMT) and Mismatch Repair (MMR) functions. Strategies to counteract TMZ resistance include its combination with poly(ADP-ribose) polymerase inhibitors (PARPi), which hamper the repair of N-methylpurines. PARPi are also investigated as monotherapy for tumors with deficiency of homologous recombination (HR). We have investigated whether PARPi may restore GSC sensitivity to TMZ or may be effective as monotherapy.

Methods

Ten human GSC lines were assayed for MMR proteins, MGMT and PARP-1 expression/activity, MGMT promoter methylation and sensitivity to TMZ or PARPi, alone and in combination. Since PTEN defects are frequently detected in GBM and may cause HR dysfunction, PTEN expression was also analyzed. The statistical analysis of the differences in drug sensitivity among the cell lines was performed using the ANOVA and Bonferroni’s post-test or the non-parametric Kruskal-Wallis analysis and Dunn’s post-test for multiple comparisons. Synergism between TMZ and PARPi was analyzed by the median-effect method of Chou and Talalay. Correlation analyses were done using the Spearman’s rank test.

Results

All GSCs were MMR-proficient and resistance to TMZ was mainly associated with high MGMT activity or low proliferation rate. MGMT promoter hypermethylation of GSCs correlated both with low MGMT activity/expression (Spearman’s test, P = 0.004 and P = 0.01) and with longer overall survival of GBM patients (P = 0.02). Sensitivity of each GSC line to PARPi as single agent did not correlate with PARP-1 or PTEN expression. Notably, PARPi and TMZ combination exerted synergistic antitumor effects in eight out of ten GSC lines and the TMZ dose reduction achieved significantly correlated with the sensitivity of each cell line to PARPi as single agent (P = 0.01).

Conclusions

The combination of TMZ with PARPi may represent a valuable strategy to reverse GSC chemoresistance.

Keywords:
Temozolomide; PARP inhibitor; Cancer stem cells; O6-methylguanine-DNA-methyltransferase; Chemoresistance