Artesunate Enhances the Antiproliferative Effect of Temozolomide on U87MG and A172 Glioblastoma Cell Lines

Georg      Karpel-Massler; Mike-Andrew      Westhoff; Richard   E.   Kast; Annika      Dwucet; Lisa      Nonnenmacher; C.   Rainer   Wirtz; Klaus-Michael      Debatin; Marc-Eric      Halatsch

Abstract

As chemotherapy with temozolomide is far from providing satisfactory clinical outcomes for patients with glioblastoma, more efficient drugs and drug combinations are urgently needed. The anti-malarial artesunate was previously shown to exert a profound cytotoxic effect on various tumor cell lines including those derived from glioblastoma. In the current study, we sought to examine the antiproliferative effect of a combination of temozolomide and artesunate on two different established human glioblastoma cell lines. The IC₅₀ and IC₂₅ were determined for temozolomide and artesunate in U87MG and A172 glioblastoma cell lines after 144 h of continuous drug exposure. The antiproliferative effect of combining both agents at IC₅₀/IC₅₀ and IC₂₅/IC₂₅ was determined by a cell viability assay. Moreover, necrosis and apoptosis were analyzed by annexin V/PI staining and flow cytometric analysis. In addition, cytostatic effects were examined by carboxyfluorescein diacetate succinimidyl ester staining and subsequent flow cytometry. In both glioblastoma cell lines, artesunate was found to enhance the antiproliferative effect exerted by temozolomide. Moreover, artesunate acted in concert with temozolomide in terms of cytostatic and necrotizing effects. These observations suggest that a combination of artesunate and temozolomide might result in increased cytotoxicity in glioblastoma.

Keywords: Artesunate, combination therapy, cytostasis, glioblastoma, necrosis, temozolomide.

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