Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Department of Clinical Oncology, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Int J Mol Sci. 2021 Oct 27;22(21):11633. doi: 10.3390/ijms222111633.
Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.
胶质母细胞瘤（GBM）是人类癌症中最致命的一种。开发针对 GBM 癌症干细胞或神经胶质瘤干细胞（GSCs）的治疗方法被认为是改善 GBM 患者预后的关键，因为这些细胞被认为是 GBM 恶性程度的罪魁祸首，具有抗药性和肿瘤起始能力。在这项研究中，我们发现叶酸拮抗剂，如甲氨蝶呤（MTX）和培美曲塞，在体外对 GSCs 具有选择性细胞毒性，但对其分化后的对应物、正常成纤维细胞或神经干细胞没有作用，而 GSCs 对抗叶酸药物高度敏感可能是由于 RFC-1/SLC19A1 的表达增加，即叶酸转运蛋白，将 MTX 转运到细胞内。值得注意的是，在体内连续移植模型中，MTX 单独使用时没有表现出抗 GSC 作用，但促进了 GSC 分化诱导剂 CEP1347 的抗 GSC 作用。这表明，叶酸代谢在 GSCs 中具有重要作用，是抗 GSC 治疗的一个有前途的靶点，细胞毒性和分化治疗的联合可能是一种有效消除癌症干细胞的新的有前途的方法。
