Induction of autophagic cell death of glioma-initiating cells by cell-penetrating d-isomer peptides consisting of Pas and the p53 C-terminus

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• 作者：Yutaka Ueda ; Fan-Yan Wei ; Taku-ichiro Hide ; Hiroyuki Michiue ; Kentaro Takayama ; Taku Kaitsuka ; Hideo Nakamura ; Keishi Makino ; Jun-ichi Kuratsu ; Shiroh Futaki ; Kazuhito Tomizawa
• 关键词：Brain ; Peptide ; Drug delivery ; Apoptosis ; Cell proliferation ; Protein transduction
• 刊名：Biomaterials
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：33
• 期：35
• 页码：9061-9069
• 全文大小：1667 K

文摘

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¡ä) consisting of a cell-penetrating peptide (FHV), penetration accelerating sequence (Pas) and C-terminus of p53 (p53C¡ä) induced the cell death of GICs. dPasFHV-p53C¡ä was effectively transduced into human GICs. The peptides dose-dependently inhibited cell growth and at 3?¦ÌM completely blocked the growth of GICs but not embryonic stem cells. Autophagic cell death was observed in the GICs treated with dPasFHV-p53C¡ä but apoptosis was not. dPasFHV without p53C¡ä showed the same effect as dPasFHV-p53C¡ä, suggesting Pas to play a critical role in the cell death of GICs. Finally, dPasFHV-p53C¡ä reduced tumor mass in mice transplanted with GICs. Peptide transduction therapy using dPasFHV-p53C¡ä could be a new method for the treatment of GBM.