5-氨基乙酰丙酸介导的光动力疗法与激酶抑制剂拉帕替尼联合使用可增强胶质母细胞瘤细胞的死亡。

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sharayu Chandratre, Daniel Merenich, Kenneth Myers, Bin Chen
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引用次数: 0

摘要

5-Aminolevulinic acid(ALA)是一种术中成像剂,已被批准用于原卟啉 IX(PpIX)荧光引导的胶质母细胞瘤(GBM)切除术。目前,它正在接受临床评估,用于完成 GBM 手术后的光动力疗法(PDT)。我们之前研究发现,表皮生长因子受体 1 和 2(EGFR 和 HER2)的临床激酶抑制剂拉帕替尼通过阻断 ABCG2(ATP 结合盒超家族 G 成员 2)介导的 PpIX 外流,增强了一组 GBM 细胞系中的 PpIX 荧光,这表明拉帕替尼具有改善 ALA 用于 GBM 手术和 PDT 的潜力。在这里,我们发现拉帕替尼通过诱导肿瘤细胞凋亡和坏死,增强了PDT诱导的细胞毒性。在未检测到 Bcl-2 且 Bcl-xL 水平较低的 H4 细胞系中,肿瘤细胞凋亡的诱导是大规模且快速的,而在 A172、U-87 和 U-118 细胞系中,肿瘤细胞凋亡的诱导则是延迟的,且程度较轻,因为这些细胞系中的促存活 Bcl-2 家族蛋白水平较高。单独使用拉帕替尼既不会降低 GBM 细胞的活力,也不会对表皮生长因子受体下游信号转导产生任何显著影响。拉帕替尼对ALA-PDT的增强作用主要是由于细胞内PpIX的增加,尤其是线粒体内PpIX的增加,从而激活了线粒体介导的H4细胞凋亡。本研究表明,拉帕替尼抑制了ABCG2介导的PpIX外流,并通过诱导肿瘤细胞死亡使GBM细胞对ALA-PDT敏感。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

5-Aminolevulinic acid-mediated photodynamic therapy in combination with kinase inhibitor lapatinib enhances glioblastoma cell death

5-Aminolevulinic acid-mediated photodynamic therapy in combination with kinase inhibitor lapatinib enhances glioblastoma cell death

5-Aminolevulinic acid (ALA) is an intraoperative imaging agent approved for protoporphyrin IX (PpIX) fluorescence-guided resection of glioblastoma (GBM). It is currently under clinical evaluation for photodynamic therapy (PDT) after the completion of GBM surgery. We previously showed that lapatinib, a clinical kinase inhibitor of epidermal growth factor receptor 1 & 2 (EGFR and HER2), enhanced PpIX fluorescence in a panel of GBM cell lines by blocking ABCG2 (ATP-binding cassette super-family G member 2)-mediated PpIX efflux, which suggests its potential for improving ALA for GBM surgery and PDT. Here we show that lapatinib enhanced PDT-induced cytotoxicity by promoting GBM cell death with the induction of apoptosis followed by necrosis. While the induction of tumor cell apoptosis was massive and rapid in the H4 cell line with no detectable Bcl-2 and a low level of Bcl-xL, it was delayed and much less in extent in A172, U-87 and U-118 cell lines with higher levels of pro-survival Bcl-2 family proteins. Lapatinib treatment alone neither reduced GBM cell viability nor had any significant effect on EGFR downstream signaling. Its enhancement of ALA–PDT was largely due to the increase of intracellular PpIX particularly in the mitochondria, resulting in the activation of mitochondria-mediated apoptosis in H4 cells. Our present study demonstrates that lapatinib inhibits ABCG2-mediated PpIX efflux and sensitizes GBM cells to ALA–PDT by inducing tumor cell death.

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来源期刊
Apoptosis
Apoptosis 生物-生化与分子生物学
CiteScore
9.10
自引率
4.20%
发文量
85
审稿时长
1 months
期刊介绍: Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.
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