gms | German Medical Science

Objective: Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults. Despite the standard therapy including surgical resection and adjuvant combined radio/chemotherapy, the average survival of GBM patients is still poor and reaches approximately 12-15 months. Thus, there is an urgent need to develop alternative treatment strategies in order to overcome the resistance against the preferred chemotherapeutic drug temozolomide (TMZ). A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of the alternative compound AT101 on two GBM cell lines (U87MG and U251MG) with a focus on the effects on tumor stem-like cells, which are often found to mediate the development of tumor recurrences.

Methods: The analysis comprised cytotoxicity assays and growth analysis, as well as the investigation of changes in signaling pathways and on the gene expression level. Furthermore, the role of the tumor microenvironment was analyzed by stimulating native cells with stem-like cell conditioned medium. The therapeutic response towards AT101 was thereby compared between treatment with TMZ or the combination of both.

Results: AT101 was found to induce strong cytotoxic effects in U251MG and U87MG stem-like cells in comparison to the respective native cells, whereas treatment with TMZ had only moderate effects on both native and stem-like cells. In addition, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with stem-like cell conditioned medium, indicating the role of the tumor microenvironment, especially the stem cell niche, on the therapeutic response of GBMs. The different responses of native cells and stem-like cells to treatment with TMZ, AT101, or a combination of both were also found to be reflected by a different activation of the Erk signaling pathway. Analysis of the expression level of various cytokine and chemokine receptors revealed that especially CXCR7 was found to be consistently downregulated in both cell lines upon stimulation of native cells.

Conclusion: The obtained results indicate that AT101 represents an alternative drug for future GBM therapy. Since the tumor stem-like cells responded strongly to treatment with AT101, this might represent a promising approach in order to kill the remaining tumor cells after resection more efficiently than the therapy with TMZ and thus, prevent the development of tumor recurrences.