gms | German Medical Science

Objective: As chemotherapy with temozolomide is far from providing satisfactory clinical outcomes for patients with glioblastoma multiforme, 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 glioblastoma cells. In the current study, we sought to examine the antiproliferative effect of a combination of temozolomide and artesunate on different established glioblastoma multiforme cell lines.

Methods: The drug concentrations achieving a 50% or 25% inhibition of tumor cell proliferation (IC50, IC25) were determined for temozolomide and artesunate in U87 and A172 glioblastoma cell lines using a cytotoxicity assay after 144 hours of continous drug exposure. In the next step, cells were subjected to a combination of both drugs at either IC50 or IC25 for the same period of time, and cell viability was determined thereafter. Drug combination effects (i.e., synergism, additivity, or antagonism) were calculated using the Bliss equation.

Results: In both glioblastoma cell lines, the combination of temozolomide and artesunate at their respective IC50 resulted in an antagonistic antiproliferative effect which was also present in A172 at IC25. Contrarily, a synergistic antiproliferative effect was noted in U87 at IC25.

Conclusions: These results represent a cautionary reminder that a successful combination of cytotoxic agents must be strictly based on mechanistic synergism. Moreover, our data suggest that the mechanism of action of temozolomide and/or artesunate may be dose-dependent.