Potentiation of temozolomide activity against glioblastoma cells by aromatase inhibitor letrozole.
Potentiation of temozolomide activity against glioblastoma cells by aromatase inhibitor letrozole.
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DOI：
10.1007/s00280-022-04469-5
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发表时间：
2022-10
影响因子：
3
通讯作者：
Desai, Pankaj B.
中科院分区：
文献类型：
--
作者：
Karve, Aniruddha S.;Desai, Janki M.;Dave, Nimita;Wise-Draper, Trisha M.;Gudelsky, Gary A.;Phoenix, Timothy N.;DasGupta, Biplab;Sengupta, Soma;Plas, David R.;Desai, Pankaj B.
DNA烷基化剂替莫唑胺（TMZ）是治疗胶质母细胞瘤（GBM）的一线药物。然而，它的使用受到耐药性和使人衰弱的不良反应的影响。之前，我们观察到来曲唑（LTZ）是一种芳香酶抑制剂，在临床前模型中对GBM具有有效的活性。在这里，我们评估了LTZ对患者源性GBM细胞的TMZ活性的影响。采用患者源性G76 （TMZ敏感）、BT142 （TMZ中敏感）以及G43和G75 （TMZ耐药）GBM系，我们评估了LTZ和TMZ对细胞活力和神经圈生长的影响。进行组合指数（CI）分析以获得这种相互作用的定量见解。然后，我们通过流式细胞术分析评估了DNA损伤效应。X的形成和诱导凋亡信号通路（caspase3/7活性）。并评价了添加雌二醇对ltz诱导的细胞毒性和DNA损伤的影响。与非细胞毒性浓度（40 nM）的LTZ共处理，G76、BT-142、G43和G75细胞的TMZ IC50分别降低了8倍、37倍、240倍和640倍。基于CI分析，认为相互作用是协同的。LTZ共处理也显著增加了TMZ的DNA损伤作用。雌二醇的加入消除了这些LTZ效应。在TMZ敏感系和TMZ抗性系中，LTZ增加DNA损伤并协同提高TMZ活性。这些作用被添加外源性雌二醇消除，强调观察到的LTZ效应可能是由雌激素剥夺介导的。我们的研究为探讨LTZ和TMZ联合治疗GBM的临床潜力提供了强有力的理论依据。
The DNA alkylating agent temozolomide (TMZ), is the first-line therapeutic for the treatment of glioblastoma (GBM). However, its use is confounded by the occurrence of drug resistance and debilitating adverse effects. Previously, we observed that letrozole (LTZ), an aromatase inhibitor, has potent activity against GBM in pre-clinical models. Here, we evaluated the effect of LTZ on TMZ activity against patient-derived GBM cells. Employing patient-derived G76 (TMZ-sensitive), BT142 (TMZ-intermediately sensitive) and G43 and G75 (TMZ-resistant) GBM lines we assessed the influence of LTZ and TMZ on cell viability and neurosphere growth. Combination Index (CI) analysis was performed to gain quantitative insights of this interaction. We then assessed DNA damaging effects by conducting flow-cytometric analysis of ˠH2A.X formation and induction of apoptotic signaling pathways (caspase3/7 activity). The effects of adding estradiol on LTZ-induced cytotoxicity and DNA damage were also evaluated. Co-treatment with LTZ at a non-cytotoxic concentration (40 nM) reduced TMZ IC50 by 8, 37, 240 and 640 folds in G76, BT-142, G43 and G75 cells, respectively. The interaction was deemed to be synergistic based on CI analysis. LTZ co-treatment also significantly increased DNA damaging effects of TMZ. Addition of estradiol abrogated these LTZ effects. LTZ increases DNA damage and synergistically enhances TMZ activity in TMZ sensitive and TMZ-resistant GBM lines. These effects are abrogated by the addition of exogenous estradiol underscoring that the observed effects of LTZ may be mediated by estrogen deprivation. Our study provides a strong rationale for investigating the clinical potential of combining LTZ and TMZ for GBM therapy.
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影响因子：
3.9
作者：
Duenas Jimenez, J. M.;Candanedo Arellano, A.;Duenas Jimenez, S. H.
通讯作者：
Duenas Jimenez, S. H.
影响因子：
15.9
作者：
Kitange, Gaspar J.;Carlson, Brett L.;Sarkaria, Jann N.
通讯作者：
Sarkaria, Jann N.
影响因子：
4.7
作者：
Gómez-Oliva R;Domínguez-García S;Carrascal L;Abalos-Martínez J;Pardillo-Díaz R;Verástegui C;Castro C;Nunez-Abades P;Geribaldi-Doldán N
通讯作者：
Geribaldi-Doldán N
DOI：
10.1158/1078-0432.ccr-09-1349
发表时间：
2009-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Portnow J;Badie B;Chen M;Liu A;Blanchard S;Synold TW
通讯作者：
Synold TW
影响因子：
3
作者：
Dave, Nimita;Gudelsky, Gary A.;Desai, Pankaj B.
通讯作者：
Desai, Pankaj B.