Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer.
Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer.
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DOI：
10.3390/cancers13102322
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发表时间：
2021-05-12
期刊：
影响因子：
5.2
通讯作者：
Benbrook DM
中科院分区：
文献类型：
--
作者：
Chandra V;Rai R;Benbrook DM
全球子宫内膜癌的发病率和死亡率正在稳步上升。复发风险高的子宫内膜癌患者接受化疗，这会导致显着的毒性。已发现分子靶向药物比化疗引起的毒性更小。我们研究了一种名为 SHetA2 的低毒性药物，它针对子宫内膜癌中高度突变的三种热休克 A 蛋白。我们的结果表明，SHetA2 可抑制子宫内膜癌细胞和肿瘤，并增强紫杉醇的治疗效果而不增加毒性。该信息支持开展临床试验，以测试 SHetA2 与紫杉醇组合是否可以在不增加毒性的情况下增加紫杉醇的治疗效果，或者允许降低紫杉醇剂量以达到相同水平的治疗效果，但毒性降低。我们关于 SHetA2 工作原理的新知识可以转化为生物标志物的开发，以预测患者最有可能从基于 SHetA2 的治疗中受益。患有晚期疾病或高复发风险的子宫内膜癌患者接受化疗。我们的目的是评估新药 SHetA2 单独使用以及与紫杉醇联合治疗子宫内膜癌的效用和机制。 SHetA2 靶向 HSPA 伴侣蛋白、Grp78、hsc70 和 mortalin，这些蛋白在子宫内膜癌中具有高突变率。在 AN3CA、Hec13b 和 Ishikawa 子宫内膜癌细胞系以及 Ishikawa 异种移植物的生长中评估了 SHetA2 对癌表型、线粒体、代谢、蛋白质表达、mortalin/客户蛋白复合物和细胞死亡的影响。在所有三种细胞系中，SHetA2 抑制贴壁依赖性生长、迁移、侵袭和 ATP 产生，并诱导 G1 细胞周期停滞、线粒体损伤以及半胱天冬酶和凋亡诱导因子 (AIF) 介导的凋亡。这些影响与参与细胞周期调节、线粒体功能、蛋白质合成、内质网应激和代谢的蛋白质水平改变有关。破坏 Mortalin 与线粒体和代谢蛋白的复合物；以及氧化磷酸化和糖酵解的抑制。 SHetA2 和紫杉醇在所有细胞系中均表现出协同组合指数，并且比单独使用任何一种药物具有更大的异种移植肿瘤生长抑制作用。 SHetA2 对培养物和体内的子宫内膜癌细胞系具有活性，并与紫杉醇协同作用。
Incidence and death rates for endometrial cancer are steadily rising world-wide. Endometrial cancer patients at high risk for recurrence are treated with chemotherapy, which causes significant toxicity. Molecularly targeted drugs have been found to cause less toxicity than chemotherapy. We studied a low-toxicity drug, called SHetA2, which targets three heat shock A proteins that are highly mutated in endometrial cancers. Our results demonstrated that SHetA2 inhibits endometrial cancer cells and tumors, and enhances therapeutic effects of paclitaxel without increasing toxicity. This information supports development of clinical trials to test if combining SHetA2 with paclitaxel can increase the paclitaxel therapeutic effect without increasing toxicity, or allows a lowered paclitaxel dose to achieve the same level of therapeutic effect, but with reduced toxicity. Our new knowledge about how SHetA2 works can be translated into development of biomarkers to predict with patients would most likely benefit from SHetA2-based therapy. Endometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78, hsc70, and mortalin, which have high mutation rates in endometrial cancer. SHetA2 effects on cancerous phenotypes, mitochondria, metabolism, protein expression, mortalin/client protein complexes, and cell death were evaluated in AN3CA, Hec13b, and Ishikawa endometrial cancer cell lines, and on growth of Ishikawa xenografts. In all three cell lines, SHetA2 inhibited anchorage-independent growth, migration, invasion, and ATP production, and induced G1 cell cycle arrest, mitochondrial damage, and caspase- and apoptosis inducing factor (AIF)-mediated apoptosis. These effects were associated with altered levels of proteins involved in cell cycle regulation, mitochondrial function, protein synthesis, endoplasmic reticulum stress, and metabolism; disruption of mortalin complexes with mitochondrial and metabolism proteins; and inhibition of oxidative phosphorylation and glycolysis. SHetA2 and paclitaxel exhibited synergistic combination indices in all cell lines and exerted greater xenograft tumor growth inhibition than either drug alone. SHetA2 is active against endometrial cancer cell lines in culture and in vivo and acts synergistically with paclitaxel.
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DOI：
10.1016/j.mrgentox.2012.03.009
发表时间：
2012-07-04
影响因子：
1.9
作者：
Doppalapudi, Rupa S.;Riccio, Edward S.;Davis, Zoe;Menda, Sean;Wang, Abraham;Du, Nicholas;Green, Carol;Kopelovich, Levy;Rao, Chinthalapally V.;Benbrook, Doris M.;Kapetanovic, Izet M.
通讯作者：
Kapetanovic, Izet M.
影响因子：
11.1
作者：
Bano D;Prehn JHM
通讯作者：
Prehn JHM
影响因子：
5.8
作者：
Bestvina, Christine M.;Fleming, Gini F.
通讯作者：
Fleming, Gini F.
影响因子：
4.7
作者：
Cella, David;Huang, Helen;Spirtos, Nick M.
通讯作者：
Spirtos, Nick M.
影响因子：
2
作者：
Cheng, Wei;Zhang, Bin;Ding, Jinhui
通讯作者：
Ding, Jinhui