Differential radiosensitizing effect of valproic acid in differentiation versus self-renewal promoting culture conditions.
Differential radiosensitizing effect of valproic acid in differentiation versus self-renewal promoting culture conditions.
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DOI：
10.1016/j.ijrobp.2009.09.052
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发表时间：
2010-03-01
影响因子：
7
通讯作者：
Woodward, Wendy A.
中科院分区：
文献类型：
--
作者：
Debeb, Bisrat G.;Xu, Wei;Mok, Henry;Li, Li;Robertson, Fredika;Ueno, Naoto T.;Reuben, Jim;Lucci, Anthony;Cristofanilli, Massimo;Woodward, Wendy A.
关键词：
研究表明，丙戊酸（VA）可增强正常造血干细胞的增殖和自我更新，并且乳腺癌干/祖细胞可以抵抗辐射。基于这些数据，我们假设 VA 无法使生长成 3D 乳腺球的乳腺癌干/祖细胞放射增敏。我们使用在干细胞促进培养条件（3D，乳腺球）和标准非干细胞单层培养条件（2D）下生长的 MCF7 乳腺癌细胞系来检查 VA 预处理对克隆存活测定中辐射敏感性以及胚胎干细胞转录因子表达的影响。 3D 培养的 MCF-7 细胞表达更高水平的 Oct4、Nanog 和 Sox2。 3D 传代丰富了 3D 微球形成测定中的自我更新并增加了放射抗性。 VA 对贴壁细胞放射敏感，但在单次克隆形成试验中对 3D 细胞进行放射防护。此外，分级辐射使 VA 处理的贴壁 MCF7 细胞敏感，但对 VA 处理的单细胞生长成微球体没有显着影响。我们得出的结论是，VA 可能比那些表达干细胞替代物的分化细胞优先对放射增敏，并且干细胞促进培养是体外评估新型癌症治疗剂和放射增敏剂的有用工具。
It has been shown that valproic acid (VA) enhances proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. Based on these data, we hypothesized that VA would fail to radiosenstize breast cancer stem/progenitor cells grown to 3D mammospheres. We used the MCF7 breast cancer cell line grown under stem cell promoting culture conditions (3D, mammosphere) and standard non-stem cell monolayer culture conditions (2D) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. 3D cultured MCF-7 cells express higher levels of Oct4, Nanog and Sox2. 3D passage enriched self-renewal and increased radioresistance in 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells, but did not have a significant effect in VA-treated single cells grown to mammospheres. We conclude that VA may preferentially radiosensitize differentiated cells over those expressing stem cell surrogates, and that stem cell promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.
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