Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation.
Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation.
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DOI：
10.1007/s10637-014-0084-7
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发表时间：
2014-08
影响因子：
3.4
通讯作者：
Cohen, Mark S.
中科院分区：
文献类型：
--
作者：
Grogan, Patrick T.;Sarkaria, Jann N.;Timmermann, Barbara N.;Cohen, Mark S.
关键词：
由于缺乏更有效的药物，替莫唑胺（TMZ）仍然是多形性胶质母细胞瘤（GBM）患者的首选化疗药物。然而，肿瘤很快对这种治疗产生耐药性，因此迫切需要替代方法和策略来重新使细胞敏感。Withaferin A （WA）是一种从茄科植物家族的几个属中提取的甾体内酯，先前在多种肿瘤模型中显示出有效的抗癌活性。在这里，我们研究了WA作为单一疗法和与TMZ联合治疗对TMZ耐药GBM细胞的影响。WA通过剂量依赖性G2/M细胞周期阻滞和内源性和外源性凋亡途径阻止GBM细胞增殖。这种效应与Akt/mTOR和MAPK存活和增殖途径主要蛋白的缺失有关，Akt、mTOR和p70 S6K磷酸化减少，但ERK1/2代偿激活。酪氨酸激酶细胞表面受体c-Met、EGFR和Her2的缺失也被观察到。通过直接测量和随后的热休克反应，通过HSP32和HSP70上调和HSF1降低，WA证明了n -乙酰- l-半胱氨酸抑制氧化应激的诱导。最后，WA预处理tmz耐药GBM细胞与o6 -甲基鸟嘌呤- dna甲基转移酶（MGMT）缺失相关，从而增强tmz介导的MGMT降解。WA和TMZ联合处理导致mgmt介导的TMZ抗性重敏，但不通过错配修复突变产生抗性。这些研究表明，在TMZ耐药的GBM中，WA作为单一疗法和与标准化疗药物TMZ联合的再增敏剂具有巨大的临床潜力。
Temozolomide (TMZ) has remained the chemotherapy of choice in patients with glioblastoma multiforme (GBM) primarily due to the lack of more effective drugs. Tumors, however, quickly develop resistance to this line of treatment creating a critical need for alternative approaches and strategies to resensitize the cells. Withaferin A (WA), a steroidal lactone derived from several genera of the Solanaceae plant family has previously demonstrated potent anti-cancer activity in multiple tumor models. Here, we examine the effects of WA against TMZ-resistant GBM cells as a monotherapy and in combination with TMZ. WA prevented GBM cell proliferation by dose-dependent G2/M cell cycle arrest and cell death through both intrinsic and extrinsic apoptotic pathways. This effect correlated with depletion of principle proteins of the Akt/mTOR and MAPK survival and proliferation pathways with diminished phosphorylation of Akt, mTOR, and p70 S6K but compensatory activation of ERK1/2. Depletion of tyrosine kinase cell surface receptors c-Met, EGFR, and Her2 was also observed. WA demonstrated induction of N-acetyl-L-cysteine-repressible oxidative stress as measured directly and through a subsequent heat shock response with HSP32 and HSP70 upregulation and decreased HSF1. Finally, pretreatment of TMZ-resistant GBM cells with WA was associated with O6-methylguanine-DNA methyltransferase (MGMT) depletion which potentiated TMZ-mediated MGMT degradation. Combination treatment with both WA and TMZ resulted in resensitization of MGMT-mediated TMZ-resistance but not resistance through mismatch repair mutations. These studies suggest great clinical potential for the utilization of WA in TMZ-resistant GBM as both a monotherapy and a resensitizer in combination with the standard chemotherapeutic agent TMZ.
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影响因子：
3.7
作者：
Khan S;Rammeloo AW;Heikkila JJ
通讯作者：
Heikkila JJ
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15.9
作者：
Kitange, Gaspar J.;Carlson, Brett L.;Sarkaria, Jann N.
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Sarkaria, Jann N.