Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control
Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control
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DOI：
10.4161/cc.11.6.19576
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发表时间：
2012-03-15
期刊：
影响因子：
4.3
通讯作者：
Valerie, Kristoffer
中科院分区：
文献类型：
--
作者：
Golding, Sarah E.;Rosenberg, Elizabeth;Valerie, Kristoffer
众所周知，多形性胶质母细胞瘤(GBM)对治疗具有耐药性。因此，迫切需要新的治疗策略。ATM可引起DNA损伤反应(DDR)，使细胞产生辐射抗性；因此，用ATM抑制剂(ATMI)靶向DDR是非常有吸引力的。在这里，我们表明，在纳摩尔范围内的动态ATM激酶抑制导致强大的人胶质瘤细胞的放射增敏，抑制生长，并不与替莫唑胺(TMZ)治疗相冲突。第二代ATMI类似物KU-60019在亚微摩尔浓度下对人胶质母细胞瘤细胞的DDR具有快速、可逆和完全的抑制作用。KU-60019抑制主要DNA损伤效应因子P53、H_2AX、KAP_1和AKT的磷酸化。集落形成放射存活实验表明，持续暴露于纳摩尔浓度的KU-60019能有效地增敏胶质母细胞瘤细胞系。当KU-60019和TMZ共同处理细胞时，注意到辐射诱导的细胞杀伤率略有增加，尽管TMZ单独无法使这些细胞对辐射增敏。此外，在没有辐射的情况下，KU-60019加或不加替马西林都会抑制胶质瘤细胞的生长，但对人胚胎干细胞来源的星形胶质细胞的存活没有显著影响。总之，ATM激酶的瞬时抑制为放射增敏GBM与标准治疗相结合提供了一种有前景的策略。此外，在没有辐射的情况下，KU-60019限制了与人星形胶质细胞共培养的胶质瘤细胞的生长，这些细胞似乎不受相同处理的影响。因此，组间生长抑制也许可以在体内实现，对大脑的不良影响很小。
Glioblastoma multiforme (GBM) is notoriously resistant to treatment. Therefore, new treatment strategies are urgently needed. ATM elicits the DNA damage response (DDR), which confers cellular radioresistance; thus, targeting the DDR with an ATM inhibitior (ATMi) is very attractive. Herein, we show that dynamic ATM kinase inhibition in the nanomolar range results in potent radiosensitization of human glioma cells, inhibits growth and does not conflict with temozolomide (TMZ) treatment. The second generation ATMi analog KU-60019 provided quick, reversible and complete inhibition of the DDR at sub-micromolar concentrations in human glioblastoma cells. KU-60019 inhibited the phosphorylation of the major DNA damage effectors p53, H2AX and KAP1 as well as AKT. Colony-forming radiosurvival showed that continuous exposure to nanomolar concentrations of KU-60019 effectively radiosensitized glioblastoma cell lines. When cells were co-treated with KU-60019 and TMZ, a slight increase in radiation-induced cell killing was noted, although TMZ alone was unable to radiosensitize these cells. In addition, without radiation, KU-60019 with or without TMZ reduced glioma cell growth but had no significant effect on the survival of human embryonic stem cell (hESC)-derived astrocytes. Altogether, transient inhibition of the ATM kinase provides a promising strategy for radiosensitizing GBM in combination with standard treatment. In addition, without radiation, KU-60019 limits growth of glioma cells in co-culture with human astrocytes that seem unaffected by the same treatment. Thus, inter-fraction growth inhibition could perhaps be achieved in vivo with minor adverse effects to the brain.