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Synergistic effects of the combined treatment of U251 and T98G glioma cells with an anti‑tubulin tetrahydrothieno[2,3‑c]pyridine derivative and a peptide nucleic acid targeting miR‑221‑3p.

International journal of oncology (2021-07-20)
Matteo Zurlo, Romeo Romagnoli, Paola Oliva, Jessica Gasparello, Alessia Finotti, Roberto Gambari
ABSTRACT

In the development of novel and more effective anticancer approaches, combined treatments appear to be of great interest, based on the possibility of obtaining relevant biological or therapeutic effects using lower concentrations of single drugs. Combination therapy may prove to be of utmost significance in the management of glioblastoma (GBM), a lethal malignancy that accounts for 42% of cancer cases of the central nervous system, with a median survival rate of 15 months. As regards novel therapeutic approaches, the authors have recently demonstrated that peptide nucleic acids (PNAs) that target microRNA (miRNA/miR)‑221 are very active in inducing the apoptosis of glioma cells. Furthermore, in a recent study, the authors described two novel series of tubulin polymerization inhibitors based on the 4,5,6,7‑tetrahydrothieno[2,3‑c]pyridine and 4,5,6,7‑tetrahydrobenzo[b]thiophene scaffold, which exerted a potent anti‑proliferative effect on a variety of tumor cell lines. The present study aimed to verify the activity on glioblastoma cancer cell lines of one of the most active compounds tested, corresponding to 2‑(3', 4', 5'‑trimethoxyanilino)‑3‑cyano/alkoxycarbonyl‑6‑substituted‑4 5,6,7‑tetrahydrothiene[2,3‑c] pyridine (compound 3b), used in combination with an anti‑miR‑221‑3p PNA, already demonstrated to be able to induce high levels of apoptosis. To the best of our knowledge, the results obtained herein demonstrate for the first time a 'combination therapy' performed by the combined use of a PNA targeting miR‑221 and the tetrahydrothiene[2,3‑c]pyridine derivative 3b, supporting the concept that the combined treatment of GBM cells with a PNA against a specific upregulated oncomiRNA (in the present study a PNA targeting miR‑221‑3p was used) and anti‑tubulin agents (in the present study derivative 3b was used) is an encouraging strategy which may be used to enhance the efficacy of anticancer therapies and at the same time, to reduce side‑effects.

MATERIALS
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Roche
Penicillin-Streptomycin, suitable for cell culture, lyophilized (clear, colorless solution after reconstitution), non-sterile; 0.2 μm filtered, sufficient for 20 mL