Effects of the anti‐tumorigenic agent at101 on human glioblastoma cells in the microenvironmental glioma stem cell niche

Abstract

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter‐ and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(‐) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem‐like cells in comparison to the respective native cells. Moreo-ver, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem‐like cell‐conditioned medium. This higher sensitivity was reflected by a specific inhib-itory influence on the p‐p42/44 signaling pathway. Further, the expression of CXCR7 and the inter-leukin‐6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.