Abstract

Glioblastoma multiforme (GBM) is a lethal malignant tumor accounting for 42% of the tumors of the central nervous system, the median survival being 15 months. At present, no curative treatment is available for GBM and new drugs and therapeutic protocols are urgently needed. In this context, combined therapy appears to be a very interesting approach. The isothiocyanate sulforaphane (SFN) has been previously shown to induce apoptosis and inhibit the growth and invasion of GBM cells. On the other hand, the microRNA miR-15b is involved in invasiveness and proliferation in GBM and its inhibition is associated with the induction of apoptosis. On the basis of these observations, the objective of the present study was to determine whether a combined treatment using SFN and a peptide nucleic acid interfering with miR-15b-5p (PNA-a15b) might be proposed for increasing the pro-apoptotic effects of the single agents. To verify this hypothesis, we have treated GMB U251 cells with SFN alone, PNA-a15b alone or their combination. The cell viability, apoptosis and combination index were, respectively, analyzed by calcein staining, annexin-V and caspase-3/7 assays, and RT-qPCR for genes involved in apoptosis. The efficacy of the PNA-a15b determined the miR-15b-5p content analyzed by RT-qPCR. The results obtained indicate that SFN and PNA-a15b synergistically act in inducing the apoptosis of U251 cells. Therefore, the PNA-a15b might be proposed in a “combo-therapy” associated with SFN. Overall, this study suggests the feasibility of using combined treatments based on PNAs targeting miRNA involved in GBM and nutraceuticals able to stimulate apoptosis.

Highlights

  • Glioblastoma multiforme (GBM) is a lethal malignant tumor accounting for 42% of the tumors of the central nervous system, the median survival being 15 months [1,2,3].At present, no curative treatment is available for GBM and the most used first-line drug, temozolomide (TMZ), is only able to cause an increase in the life expectancy of the treated patients, though this is still not satisfactory [4]

  • We have recently demonstrated that the treatment of glioblastoma cell lines with peptide nucleic acids (PNAs) targeting anti-apoptotic microRNAs leads to the induction of the apoptosis of glioblastoma cell lines, such as U251 and T98G cell lines

  • In view of testing a combination of SFN and R8-PNA-a15b, we first analyzed the effect of an increasing concentration of SFN on U251 cells to establish the contribution of SFN alone to apoptosis in our cell model

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Summary

Introduction

Glioblastoma multiforme (GBM) is a lethal malignant tumor accounting for 42% of the tumors of the central nervous system, the median survival being 15 months [1,2,3].At present, no curative treatment is available for GBM and the most used first-line drug, temozolomide (TMZ), is only able to cause an increase in the life expectancy of the treated patients, though this is still not satisfactory [4]. New drugs are urgently needed for determining their possible employment in therapeutic protocols for anti-GBM treatments, tackling important issues of the GBM management, such as the development of drug resistance [5,6,7,8,9,10] In this context, combined therapy appears to be a very interesting approach for gliomas and other tumors [11,12,13,14,15]. Side effects might be significantly lower when combined treatments are employed [11] Another very interesting possibility is that combined treatments might allow us to limit the issue of drug resistance, which is an impacting feature of several cancers [11,12,15]. A high proportion of GBMs become TMZ-resistant with time [7,8,9,10]

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