Caylioglu Deniz, Meyer Rieke Johanna, Hellmold Dana, Kubelt Carolin, Synowitz Michael, Held-Feindt Janka
Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
Int J Mol Sci. 2021 Mar 30;22(7):3606. doi: 10.3390/ijms22073606.
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.
胶质母细胞瘤（GBM）因其具有高度的化学抗性而几乎无法治疗。由特殊的微环境生态位和不同的肿瘤细胞亚群所反映出的显著的瘤间和瘤内异质性，使得GBM能够逃避治疗方案。因此，迫切需要开发替代治疗策略。AT101（棉酚的R(-)对映体）是治疗GBM的一个有前景的候选药物。本研究在两种GBM细胞系（U251MG和U87MG）的微环境胶质瘤干细胞生态位模型中评估了AT101单独或与替莫唑胺（TMZ）联合使用的效果。与各自的原始细胞相比，发现AT101对U251MG和U87MG干细胞样细胞具有强烈的细胞毒性作用。此外，在用干细胞样细胞条件培养基孵育原始细胞后，观察到对AT101治疗具有更高的敏感性。这种更高的敏感性通过对p-p42/44信号通路的特异性抑制作用得以体现。此外，在这些刺激条件下，CXCR7和白细胞介素-6受体的表达受到显著调节。由于已知肿瘤干细胞样细胞介导肿瘤复发的发生，并且观察到它们对AT101治疗有强烈反应，这可能代表了一种预防GBM复发的有前景的方法。
