Comparative analysis of the effects of a sphingosine kinase inhibitor to temozolomide and radiation treatment on glioblastoma cell lines.
Comparative analysis of the effects of a sphingosine kinase inhibitor to temozolomide and radiation treatment on glioblastoma cell lines.
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DOI：
10.1080/15384047.2017.1323583
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发表时间：
2017-06-03
影响因子：
3.6
通讯作者：
Dokic I
中科院分区：
文献类型：
--
作者：
Oancea-Castillo LR;Klein C;Abdollahi A;Weber KJ;Régnier-Vigouroux A;Dokic I
多形性胶质母细胞瘤（GBM）由于其显著的细胞异质性，对替莫唑胺（TMZ）联合放疗的标准治疗表现出高度耐药性。因此，需要靶向增强特异性GBM自分泌或旁分泌机制并放大标准治疗效果的替代分子。1-磷酸鞘氨醇（S1 P）是一种脂质靶向分子，在细胞侵袭和增殖中起重要作用。鞘氨醇激酶抑制剂（SKI）可防止S1 P形成并诱导活性氧（ROS）产生增加，这可能增强辐射细胞毒性。我们分析了SKI单一与TMZ和辐射联合治疗对2种人GBM细胞系的影响，其特征在于缺乏MGMT表达和抗氧化酶谷胱甘肽过氧化物酶1（GPx 1）的低或高表达。作用是药物浓度，细胞系依赖性和部分ROS介导的。克隆形成存活试验表明SKI比TMZ更有效地增加表达低量GPx 1的U87细胞对2戈伊X射线剂量的敏感性。与替莫唑胺/放射的组合相比，SKI和TMZ的添加显著降低了U87细胞的存活率。SKI对2戈伊X射线剂量的致敏效果不如TMZ。在无辐射条件下，其与TMZ的结合与TMZ与X射线的结合一样有效。我们为SKI作为TMZ的替代或补充治疗以及低剂量药物和X射线的有效组合提供了第一个证据。这些可能有助于作为新的双模式和三模式疗法来对抗GBM异质性。
Glioblastoma multiforme (GBM) exhibits high resistance to the standard treatment of temozolomide (TMZ) combined with radiotherapy, due to its remarkable cell heterogeneity. Accordingly, there is a need to target alternative molecules enhancing specific GBM autocrine or paracrine mechanisms and amplifying the effect of standard treatment. Sphingosine 1-phosphate (S1P) is such a lipid target molecule with an important role in cell invasion and proliferation. Sphingosine kinase inhibitors (SKI) prevent S1P formation and induce increased production of reactive oxygen species (ROS), which may potentiate radiation cytotoxicity. We analyzed the effect of SKI singular versus combined treatments with TMZ and radiation on 2 human GBM cell lines characterized by a lack of MGMT expression and low or high expression of the anti-oxidant enzyme, glutathione peroxidase 1 (GPx1). Effects were drug concentration-, cell line-dependent and partly ROS-mediated. Clonogenic survival assay demonstrates that SKI was more effective than TMZ in increasing the sensitivity of U87 cells, which express low GPx1 amount, to a 2 Gy X-ray dose. Addition of both SKI and TMZ drastically decreased U87 cells survival compared with the combination temozolomide/radiation. SKI less effectively than TMZ sensitized LN229 cells to the 2 Gy X-ray dose. Its combination to TMZ in absence of irradiation was as efficient as TMZ combination with X-ray. We provide first evidence for SKI as an alternative or complementary treatment to TMZ, and for efficient combinations of low doses of drugs and X-ray. These may help as novel bi-modal and tri-modal therapies to contend with GBM heterogeneity.
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胶质母细胞瘤多形：外观其异质性。
影响因子：
5.2
作者：
Inda MM;Bonavia R;Seoane J
通讯作者：
Seoane J
DOI：
10.1016/s0360-3016(98)00105-9
发表时间：
1998-07-01
影响因子：
7
作者：
Latz, D;Fleckenstein, K;Weber, KJ
通讯作者：
Weber, KJ
影响因子：
45.3
作者：
Gilbert, Mark R.;Wang, Meihua;Mehta, Minesh P.
通讯作者：
Mehta, Minesh P.
影响因子：
7.4
作者：
Lin, Chien-Ju;Lee, Chin-Cheng;Shih, Chwen-Ming
通讯作者：
Shih, Chwen-Ming
影响因子：
9.7
作者：
Joseph, Justin V.;Conroy, Siobhan;Kruyt, Frank A. E.
通讯作者：
Kruyt, Frank A. E.