Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10-fold more cytotoxic to glioma stem cells (GSC) than TMZ, and is active against TMZ-resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression. Mol Cancer Ther; 17(3); 625–37. ©2018 AACR.

中文翻译：

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NEO212抑制胶质瘤干细胞的迁移和侵袭

多形性胶质母细胞瘤是一种恶性脑肿瘤，以其广泛的血管分布、侵袭性和高度侵袭性而闻名，表明细胞迁移在肿瘤进展中发挥着重要作用。GBM 的不良预后与肿瘤复发率高以及对标准治疗化疗替莫唑胺 (TMZ) 的耐药性相关。新型化合物 NEO212 是 TMZ 和紫苏醇 (POH) 的结合物，已被证明对神经胶质瘤干细胞 (GSC) 的细胞毒性比 TMZ 高 10 倍，并且对 TMZ 耐药的肿瘤细胞具有活性。在这项研究中，我们表明 NEO212 减少了间充质 USC02 和原神经 USC04 群体中患者来源的 GSC 原代培养物的迁移和侵袭。NEO212 减少迁移和侵袭的机制似乎与其 DNA 烷基化作用无关，这种作用在治疗的最初几个小时内会引起细胞毒性，并且与 FAK/Src 信号通路的减少有关，而 TMZ 则没有表现出这种作用。NEO212 还会降低基质金属蛋白酶 MMP2 和 MMP9 的产生，这对 GSC 侵袭至关重要。上皮和间质标记物的基因表达分析表明，NEO212 增加了上皮样特征的表达，表明上皮-间质转化过程的逆转。此外，在体内原位神经胶质瘤模型中，NEO212 通过减少 GSC 的侵袭来减少肿瘤进展，从而延长小鼠的生存时间。这些研究表明，NEO212除了具有细胞毒性外，还可以有效减少GSC的迁移和侵袭，从而在减少侵袭和恶性胶质瘤进展方面表现出重要的临床价值。摩尔癌症治疗；17(3)；625–37。©2018 AACR。