The HSP90 inhibitor ganetespib: A potential effective agent for Acute Myeloid Leukemia in combination with cytarabine.
The HSP90 inhibitor ganetespib: A potential effective agent for Acute Myeloid Leukemia in combination with cytarabine.
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DOI：
10.1016/j.leukres.2015.03.016
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发表时间：
2015-06
影响因子：
2.7
通讯作者：
Zabkiewicz, J.
中科院分区：
文献类型：
--
作者：
Lazenby, M.;Hills, R.;Burnett, A. K.;Zabkiewicz, J.
关键词：
Ganetespib是原发性AML原始细胞中的高效HSP 90抑制剂。凋亡诱导与促存活蛋白AKT的抑制是协调的。与AraC的协同相互作用抑制促存活靶标HSP 70和AKT。为在AML中进一步临床评估ganetespib提供了强有力的依据。HSP 90是一种参与调节大量细胞过程的多客户分子伴侣，并且通常在许多不同的癌症类型（包括血液恶性肿瘤）中过表达。HSP 90的抑制有望靶向多种分子异常，因此是异质性恶性肿瘤如急性髓性白血病（AML）的有吸引力的靶点。加奈替匹是一种高效的第二代HSP 90抑制剂，我们发现与阿糖胞苷相比，在纳摩尔浓度下，加奈替匹对原发性AML母细胞显著更有效（p < 0.001）。观察到剂量依赖性细胞毒性，其中凋亡反应与通过客户蛋白AKT的促存活信号传导的损失相协调。用ganetespib和阿糖胞苷联合治疗原代母细胞在一系列药物效应中显示出良好的协同相互作用（联合指数（CI）：0.47），并伴有HSP 70反馈和AKT信号传导水平的降低。总之，我们显示ganetespib作为单药治疗在原发性AML中具有高活性，并且当与阿糖胞苷联合时具有协同关系。与其他HSP 90抑制剂相比，细胞毒性细胞死亡、细胞保护/耐药机制（如AKT）抑制和临床毒性降低的组合为ganetespib在AML中的临床评估提供了强有力的依据。
Ganetespib is a highly potent HSP90 inhibitor in primary AML blasts. Apoptotic induction is co-ordinate with suppression of pro-survival protein AKT. Synergistic interaction with AraC suppressing pro-survival targets HSP70 and AKT. Provides strong rationale for further clinical assessment of ganetespib in AML. HSP90 is a multi-client chaperone involved in regulating a large array of cellular processes and is commonly overexpressed in many different cancer types including hematological malignancies. Inhibition of HSP90 holds promise for targeting multiple molecular abnormalities and is therefore an attractive target for heterogeneous malignancies such as Acute Myeloid Leukemia (AML). Ganetespib is a highly potent second generation HSP90 inhibitor which we show is significantly more effective against primary AML blasts at nanomolar concentrations when compared with cytarabine (p < 0.001). Dose dependant cytotoxicity was observed with an apoptotic response coordinate with the loss of pro-survival signaling through the client protein AKT. Combination treatment of primary blasts with ganetespib and cytarabine showed good synergistic interaction (combination index (CI): 0.47) across a range of drug effects with associated reduction in HSP70 feedback and AKT signaling levels. In summary, we show ganetespib to have high activity in primary AMLs as a monotherapy and a synergistic relationship with cytarabine when combined. The combination of cytotoxic cell death, suppression of cytoprotective/drug resistance mechanisms such as AKT and reduced clinical toxicity compared to other HSP90 inhibitors provide strong rationale for the clinical assessment of ganetespib in AML.
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影响因子：
--
作者：
Chen Y;Chen J;Loo A;Jaeger S;Bagdasarian L;Yu J;Chung F;Korn J;Ruddy D;Guo R;McLaughlin ME;Feng F;Zhu P;Stegmeier F;Pagliarini R;Porter D;Zhou W
通讯作者：
Zhou W
影响因子：
20.3
作者：
Okawa, Yutaka;Hideshima, Teru;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
3.7
作者：
Proia DA;Foley KP;Korbut T;Sang J;Smith D;Bates RC;Liu Y;Rosenberg AF;Zhou D;Koya K;Barsoum J;Blackman RK
通讯作者：
Blackman RK
影响因子：
3.8
作者：
Goldman, Jonathan W.;Raju, Robert N.;Rosen, Lee S.
通讯作者：
Rosen, Lee S.
影响因子：
20.3
作者：
Frelin, C;Imbert, V;Peyron, JF
通讯作者：
Peyron, JF