Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche.

Deniz Caylioglu,Dana Hellmold,Janka Held-Feindt,Carolin Kubelt,Michael Synowitz,Rieke Johanna Meyer

doi:10.3390/ijms22073606

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. Moreover, 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 inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-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.

Highlights

Glioblastomas (GBMs) are highly malignant primary intracranial tumors that are characterized by rapid and infiltrative progression
We compared the influence of an AT101, TMZ, or a combinational treatment of both on the survival of native and stem-like U251MG and U87MG GBM cells by cytotoxicity assays (Figure 1A–D) and determination of proliferation (Figure 2A–D) for up to six days, respectively
Stem-like and native GBM cell cultures were established and intensively characterized as described before [17,30,31,32]. Both native U251MG and U87MG cells responded only moderately to solely applied TMZ (50 μM) treatment for up to six days (15–20% dead cells) (Figure 1A,B). This effect could be slightly enhanced by the combinational treatment with TMZ (50 μM) and AT101 (5 μM), especially after six days of treatment (25–35% dead cells)

Summary

Introduction

Glioblastomas (GBMs) are highly malignant primary intracranial tumors that are characterized by rapid and infiltrative progression. The different tumor cell subpopulations communicate either directly or indirectly with e.g., tunneling nanotubes, multiple kinds of extracellular vesicles, or several (inflammatory) mediators like cytokines and chemokines [10,11,12]. They evolve in and adapt to their conquered microcompartment and, as a result, manage to evade, e.g., from suitable treatment schedules [13]. Besides the preferred chemotherapeutic drug temozolomide (TMZ), a promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of the naturally occurring cottonseed-derived polyphenol gossypol [14,15,16,17,18,19,20]

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Results

Discussion

Conclusion