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胶束化环杷明与替莫唑胺联合治疗通过下调Gli1抑制胶质母细胞瘤生长。

Combination therapy with micellarized cyclopamine and temozolomide attenuate glioblastoma growth through Gli1 down-regulation.

作者信息

Liu Yu-Jie, Ma Ying-Cong, Zhang Wen-Jie, Yang Zhen-Zhen, Liang De-Sheng, Wu Zhi-Fu, Qi Xian-Rong

机构信息

Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.

School of Materials Science and Engineering, Baise University, Guangxi Baise, 533000, PR China.

出版信息

Oncotarget. 2017 Jun 27;8(26):42495-42509. doi: 10.18632/oncotarget.17205.

DOI:10.18632/oncotarget.17205
PMID:28477008
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5522083/
Abstract

Glioblastoma multiforme (GBM) is the most common and deadly brain cancer, characterized by its aggressive proliferation to adjacent tissue and high recurrence rate. We studied the efficacy and related mechanisms of the combination of cyclopamine (Cyp, a Sonic-hedgehog pathway (Shh) inhibitor) and temozolomide (TMZ, the clinically most used chemotherapeutic agent) in anti-GBM treatment. The micellarized Cyp (MCyp) showed better performance than Cyp solution in inhibiting GBM cells proliferation (3.77-fold against U87 MG cells and 3.28-fold against DBTRG-05MG cells) and clonogenity (1.35-fold against U87 MG cells and 2.17-fold against DBTRG-05MG cells), and preferred behavior of inhibiting cell invasion, colony formation through attenuated Gli1 expression. In addition, combination of MCyp and TMZ exhibited synergistic cytotoxicity, correlating with their ability in inducing apoptosis and eliminating neurospheres formation, and the combination of TMZ was accompanied with the enhanced blockage of Shh pathway. The optimal ratio of MCyp combined to TMZ was 1:20. So we proposed to use TMZ to kill tumor parenchyma and MCyp as the cancer stem cells inhibitor to resist tumor recurrence. These findings demonstrated that combination of TMZ with micellarized Cyp is a promising strategy for exerting different functions of drugs for tumor treatment.

摘要

多形性胶质母细胞瘤（GBM）是最常见且致命的脑癌，其特征是向邻近组织侵袭性增殖且复发率高。我们研究了环杷明（Cyp，一种音猬因子信号通路（Shh）抑制剂）与替莫唑胺（TMZ，临床上最常用的化疗药物）联合用于抗GBM治疗的疗效及相关机制。胶束化环杷明（MCyp）在抑制GBM细胞增殖（对U87 MG细胞的抑制倍数为3.77倍，对DBTRG - 05MG细胞为3.28倍）和克隆形成能力（对U87 MG细胞为1.35倍，对DBTRG - 05MG细胞为2.17倍）方面表现优于Cyp溶液，并且通过减弱Gli1表达在抑制细胞侵袭、集落形成方面具有更好的表现。此外，MCyp与TMZ联合表现出协同细胞毒性，这与其诱导凋亡和消除神经球形成的能力相关，并且TMZ联合使用伴随着Shh信号通路阻断增强。MCyp与TMZ联合的最佳比例为1:20。因此，我们建议使用TMZ杀死肿瘤实质，使用MCyp作为癌症干细胞抑制剂来抵抗肿瘤复发。这些发现表明，TMZ与胶束化Cyp联合是一种有望发挥不同药物功能用于肿瘤治疗的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/5f176edb6c6e/oncotarget-08-42495-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/797e3371901a/oncotarget-08-42495-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/1132e16286ff/oncotarget-08-42495-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/486d43084124/oncotarget-08-42495-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/ec0e20e169cf/oncotarget-08-42495-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/5f176edb6c6e/oncotarget-08-42495-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/9d144ffe5be1/oncotarget-08-42495-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/ba1ceea21137/oncotarget-08-42495-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/f2560385f02a/oncotarget-08-42495-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/d41be918feb5/oncotarget-08-42495-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/2a93015d8bea/oncotarget-08-42495-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/797e3371901a/oncotarget-08-42495-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/1132e16286ff/oncotarget-08-42495-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/486d43084124/oncotarget-08-42495-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/ec0e20e169cf/oncotarget-08-42495-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/5522083/5f176edb6c6e/oncotarget-08-42495-g010.jpg

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