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新型N-乙酰丙氨酸前药在体外对前列腺癌细胞选择性诱导凋亡的评估。

In vitro evaluation of novel N-acetylalaninate prodrugs that selectively induce apoptosis in prostate cancer cells.

作者信息

McGoldrick Christopher A, Jiang Yu-Lin, Brannon Marianne, Krishnan Koyamangalath, Stone William L

机构信息

Department of Pediatrics, East Tennessee State University, Johnson City, TN 37614-0578, USA.

出版信息

BMC Cancer. 2014 Sep 18;14:675. doi: 10.1186/1471-2407-14-675.

Abstract

BACKGROUND

Cancer cell esterases are often overexpressed and can have chiral specificities different from that of the corresponding normal cells and can, therefore, be useful targets for activating chemotherapeutic prodrug esters. Prodrug esters are inactive compounds that can be preferentially activated by esterase enzymes. Moreover, cancer cells often exhibit a high level of intrinsic oxidative stress due to an increased formation of reactive oxygen species (ROS) and a decreased expression of some enzymatic antioxidants. Prodrugs designed to induce additional oxidative stress can selectively induce apoptosis in cancer cells already exhibiting a high level of intrinsic oxidative stress. This study focused on the in vitro evaluation of four novel prodrug esters: the R- and S- chiral esters of 4-[(nitrooxy)methyl]phenyl N-acetylalaninate (R- and S-NPAA) and the R- and S- chiral esters of 4-[(nitrooxy)methyl]naphth-1-yl N-acetylalaninate (R- and S-NQM), which are activated, to varying extents, by oxidized protein hydrolase (OPH, EC 3.4.19.1) yielding a quinone methide (QM) intermediate capable of depleting glutathione (GSH), a key intracellular antioxidant. OPH is a serine esterase/protease that is overexpressed in some human tumors and cancer cell lines.

METHODS

To evaluate the chiral ester prodrugs, we monitored cellular GSH depletion, cellular protein carbonyl levels (an oxidative stress biomarker) and cell viability in tumorigenic and nontumorigenic prostate cancer cell lines.

RESULTS

We found that the prodrugs were activated by OPH and subsequently depleted GSH. The S-chiral ester of NPAA (S-NPAA) was two-fold more effective than the R-chiral ester (R-NPAA) in depleting GSH, increasing oxidative stress, inducing apoptosis, and decreasing cell viability in tumorigenic prostate LNCaP cells but had little effect on non-tumorigenic RWPE-1 cells. In addition, we found that that S-NPAA induced apoptosis and decreased cell viability in tumorigenic DU145 and PC3 prostate cell lines. Similar results were found in a COS-7 model that overexpressed active human OPH (COS-7-OPH).

CONCLUSIONS

Our results suggest that prostate tumors overexpressing OPH and/or exhibiting a high level of intrinsic oxidative stress may be susceptible to QM generating prodrug esters that are targeted to OPH with little effect on non-tumorigenic prostate cells.

摘要

背景

癌细胞酯酶通常过表达,其手性特异性可能与相应正常细胞不同,因此可成为激活化疗前药酯的有用靶点。前药酯是无活性的化合物,可被酯酶优先激活。此外,由于活性氧(ROS)生成增加和一些酶促抗氧化剂表达降低,癌细胞通常表现出高水平的内在氧化应激。设计用于诱导额外氧化应激的前药可在已表现出高水平内在氧化应激的癌细胞中选择性诱导凋亡。本研究聚焦于四种新型前药酯的体外评估:4-[(硝基氧基)甲基]苯基N-乙酰丙氨酸酯(R-和S-NPAA)的R-和S-手性酯以及4-[(硝基氧基)甲基]萘-1-基N-乙酰丙氨酸酯(R-和S-NQM)的R-和S-手性酯,它们在不同程度上被氧化蛋白水解酶(OPH,EC 3.4.19.1)激活,生成能够消耗关键细胞内抗氧化剂谷胱甘肽(GSH)的醌甲基化物(QM)中间体。OPH是一种丝氨酸酯酶/蛋白酶,在一些人类肿瘤和癌细胞系中过表达。

方法

为评估手性酯前药,我们监测了致瘤性和非致瘤性前列腺癌细胞系中的细胞内GSH消耗、细胞蛋白羰基水平(一种氧化应激生物标志物)和细胞活力。

结果

我们发现前药被OPH激活,随后消耗GSH。NPAA的S-手性酯(S-NPAA)在消耗GSH、增加氧化应激、诱导凋亡和降低致瘤性前列腺LNCaP细胞的细胞活力方面比R-手性酯(R-NPAA)有效两倍,但对非致瘤性RWPE-1细胞几乎没有影响。此外,我们发现S-NPAA在致瘤性DU145和PC3前列腺癌细胞系中诱导凋亡并降低细胞活力。在过表达活性人OPH的COS-7模型(COS-7-OPH)中也发现了类似结果。

结论

我们的结果表明,过表达OPH和/或表现出高水平内在氧化应激的前列腺肿瘤可能对靶向OPH的QM生成前药酯敏感,而对非致瘤性前列腺细胞影响很小。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b03/4180535/7a2ced02d3ed/12885_2014_4866_Fig1_HTML.jpg

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