Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy
Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy
复制标题
DOI：
10.1212/wnl.0b013e318212a89f
复制
发表时间：
2011-03-01
期刊：
影响因子：
9.9
通讯作者：
Bota, Daniela A.
中科院分区：
文献类型：
--
作者：
Gong, Xing;Schwartz, Philip H.;Bota, Daniela A.
目的：新的数据表明，胶质瘤干细胞样细胞（GSCs）和神经干细胞/祖细胞（NSCs）可能具有共同的起源。GSCs驱动肿瘤增殖，似乎对传统化疗具有耐药性，而化疗对NSCs的影响尚未得到很好的研究。随着神经干细胞在学习和记忆中的作用被越来越多地认识到，我们需要找到减少神经毒性但仍然有效对抗神经胶质肿瘤的药物。方法：用替莫唑胺（TMZ）和顺铂（CIS），以及2种较新的、有前景的药物：蛋白酶体抑制剂硼替佐米（BTZ）和表皮生长因子受体酪氨酸激酶抑制剂厄洛替尼（ERL）处理3个人NSC培养物和多个低级别和高级别GSC培养物。我们测量了细胞存活、增殖、细胞死亡诱导和耐药标志物。结果：TMZ降低NSC活力，但对GSCs影响最小。TMZ诱导NSC死亡，部分由增殖增加补偿。CIS也有类似的效果。NSC对TMZ和CIS的敏感性与多药耐药基因ABCG2的低表达相关，而与MGMT或MSH1/MLH2的低表达无关。BTZ导致GSCs减少80%，而对NSCs的影响最小。BTZ治疗后GSCs的蛋白酶体水平和活性降低。ERL处理也降低了GSC数量，但没有降低NSC活力，这与NSCs中EGFR表达较低有关。结论：较新的化疗药物ERL和BTZ对GSCs有效，但对NSCs的影响很小，而较老的药物TMZ和CIS对NSCs的毒性大于对GSCs的毒性。鉴定和测试更多的选择性药物显然是必要的。神经病学(R) 2011；76: 1126 - 1134
Objectives: New data suggest that glioma stem-like cells (GSCs) and neural stem/progenitor cells (NSCs) may share common origins. GSCs drive tumor proliferation and appear to be resistant to classic chemotherapy, while the effects of chemotherapy on NSCs are not well studied. As the role of NSCs in learning and memory is increasingly recognized, we need to identify drugs that reduce neurotoxicity but are still effective against glial tumors.Methods: We treated 3 human NSC cultures and multiple low-and high-grade GSC cultures with the commonly used agents temozolomide (TMZ) and cisplatin (CIS), and with 2 newer, promising drugs: the proteasome inhibitor bortezomib (BTZ) and the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL). We measured cell survival, proliferation, cell death induction, and drug resistance markers.Results: TMZ decreased NSC viability, while minimally affecting GSCs. TMZ induced NSC death, which was partially compensated for by increased proliferation. CIS had similar effects. The NSC's sensitivity to TMZ and CIS correlated with low expression of the multidrug resistance gene ABCG2, but not of MGMT or MSH1/MLH2. BTZ caused an 80% decrease in GSCs, while minimally affecting NSCs. GSCs had lower proteasome levels and activity after BTZ treatment. ERL treatment also decreased GSC numbers, but not NSC viability, which correlated with low EGFR expression in NSCs compared to GSCs.Conclusions: Newer chemotherapy agents ERL and BTZ are effective against GSCs yet produce minimal effects on NSCs, while the older drugs TMZ and CIS are more toxic for NSCs than for GSCs. The identification and testing of more selective drugs is clearly warranted. Neurology (R) 2011; 76: 1126-1134