Department of Molecular Physiology, Kumamoto University, 1-1-1 Honjyo, Chuo-ku, Kumamoto 860-8556, Japan.
Biomaterials. 2012 Dec;33(35):9061-9. doi: 10.1016/j.biomaterials.2012.09.003. Epub 2012 Sep 21.
Glioblastoma multiforme (GBM) is the most aggressive and fatal brain tumor. GBM is resistant to chemotherapy and radiation. Recent studies have shown that glioma-initiating cells (GICs), which have characteristics of cancer stem cells, are responsible for the resistance to chemotherapy and radiation and regrowth. No effective therapy for GICs has been developed. Here we showed that D-isomer peptides (dPasFHV-p53C') consisting of a cell-penetrating peptide (FHV), penetration accelerating sequence (Pas) and C-terminus of p53 (p53C') induced the cell death of GICs. dPasFHV-p53C' was effectively transduced into human GICs. The peptides dose-dependently inhibited cell growth and at 3 μM completely blocked the growth of GICs but not embryonic stem cells. Autophagic cell death was observed in the GICs treated with dPasFHV-p53C' but apoptosis was not. dPasFHV without p53C' showed the same effect as dPasFHV-p53C', suggesting Pas to play a critical role in the cell death of GICs. Finally, dPasFHV-p53C' reduced tumor mass in mice transplanted with GICs. Peptide transduction therapy using dPasFHV-p53C' could be a new method for the treatment of GBM.
多形性胶质母细胞瘤（GBM）是最具侵袭性和致命性的脑肿瘤。GBM 对化疗和放疗具有抗性。最近的研究表明，具有癌症干细胞特征的神经胶质瘤起始细胞（GICs）是导致化疗和放疗耐药以及复发的原因。目前尚未开发出针对 GICs 的有效治疗方法。在这里，我们展示了由细胞穿透肽（FHV）、穿透加速序列（Pas）和 p53 的 C 末端（p53C'）组成的 D-异构体肽（dPasFHV-p53C'）诱导 GIC 细胞死亡。dPasFHV-p53C'有效地转导到人类 GIC 中。这些肽剂量依赖性地抑制细胞生长，在 3μM 时完全阻断 GIC 的生长，但不阻断胚胎干细胞的生长。用 dPasFHV-p53C'处理的 GIC 中观察到自噬性细胞死亡，但没有观察到细胞凋亡。没有 p53C'的 dPasFHV 表现出与 dPasFHV-p53C'相同的效果，表明 Pas 在 GIC 细胞死亡中发挥关键作用。最后，dPasFHV-p53C'减少了移植 GIC 的小鼠的肿瘤体积。使用 dPasFHV-p53C'的肽转导治疗可能是治疗 GBM 的一种新方法。
