Ribonucleases as potential modalities in anticancer therapy.
Ribonucleases as potential modalities in anticancer therapy.
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DOI：
10.1016/j.ejphar.2009.06.067
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发表时间：
2009-12-25
影响因子：
5
通讯作者：
Darzynkiewicz, Zbigniew
中科院分区：
文献类型：
--
作者：
Ardelt, Wojciech;Ardelt, Barbara;Darzynkiewicz, Zbigniew
抗肿瘤核糖核酸酶是小的（10 - 28 kDa）碱性蛋白质。它们在核糖核酸酶A和T1超家族的成员中被发现。它们的细胞毒性特性由酶活性赋予，即，催化RNA中磷酸二酯键裂解的能力。它们与带负电荷的细胞膜结合，通过内吞作用进入细胞，并转移到胞质溶胶中，在胞质溶胶中它们逃避哺乳动物蛋白核糖核酸酶抑制剂并降解RNA。在这里，我们讨论的结构，功能和抗肿瘤活性的几种细胞毒性核糖核酸酶的机制，特别强调两栖动物Onconase，这一类的唯一的酶，达到临床试验。Onconase是最小的，非常稳定，催化效率较低，比大多数RNase A同源物更具细胞毒性。其细胞抑制、细胞毒和抗癌作用已被广泛研究。它靶向tRNA、rRNA、mRNA以及非编码RNA（microRNA）。许多癌症细胞系对Onconase敏感;用10 - 100 nM酶治疗它们会导致细胞周期进展受到抑制，主要是通过G1，随后是细胞凋亡或细胞衰老。Onconase在动物模型中也具有抗癌特性。这种酶的许多作用与其关键靶点之一的microRNA一致。Onconase使细胞对多种抗癌方式敏感，并且这种性质特别令人感兴趣，表明其在治疗不同肿瘤中作为化疗或放疗的辅助剂的应用。以Onconase为例的细胞毒性RNA酶代表了一类新的抗肿瘤药物，其作用机制与目前临床上使用的药物完全不同。需要进一步的动物模型研究，包括人肿瘤移植到严重联合免疫缺陷（SCID）小鼠和临床试验，以探索细胞毒性RNA酶的临床潜力。
Antitumor ribonucleases are small (10–28 kDa) basic proteins. They were found among members of both, ribonuclease A and T1 superfamilies. Their cytotoxic properties are conferred by enzymatic activity, i.e., the ability to catalyze cleavages of phosphodiester bonds in RNA. They bind to negatively charged cell membrane, enter cells by endocytosis and translocate to cytosol where they evade mammalian protein ribonuclease inhibitor and degrade RNA. Here, we discuss structures, functions and mechanisms of antitumor activity of several cytotoxic ribonucleases with particular emphasis to the amphibian Onconase, the only enzyme of this class that reached clinical trials. Onconase is the smallest, very stable, less catalytically efficient and more cytotoxic than most RNase A homologues. Its cytostatic, cytotoxic and anticancer effects were extensively studied. It targets tRNA, rRNA, mRNA as well as the non-coding RNA (microRNAs). Numerous cancer lines are sensitive to Onconase; their treatment with 10 – 100 nM enzyme leads to suppression of cell cycle progression, predominantly through G1, followed by apoptosis or cell senescence. Onconase also has anticancer properties in animal models. Many effects of this enzyme are consistent with the microRNAs, one of its critical targets. Onconase sensitizes cells to a variety of anticancer modalities and this property is of particular interest, suggesting its application as an adjunct to chemotherapy or radiotherapy in treatment of different tumors. Cytotoxic RNases as exemplified by Onconase represent a new class of antitumor agents, with an entirely different mechanism of action than the drugs currently used in the clinic. Further studies on animal models including human tumors grafted on severe combined immunodefficient (SCID) mice and clinical trials are needed to explore clinical potential of cytotoxic RNases.
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影响因子：
4.3
作者：
Ardelt, Barbara;Ardelt, Wojciech;Darzynkiewicz, Zbigniew
通讯作者：
Darzynkiewicz, Zbigniew
DOI：
10.1111/j.1365-2184.1988.tb00855.x
发表时间：
1988-05-01
期刊：
CELL AND TISSUE KINETICS
影响因子：
--
作者：
DARZYNKIEWICZ, Z;CARTER, SP;SHOGEN, K
通讯作者：
SHOGEN, K
影响因子：
13.8
作者：
DALESSIO, G;DIDONATO, A;PARENTE, A
通讯作者：
PARENTE, A
影响因子：
2.9
作者：
CAPASSO, S;GIORDANO, F;ZAGARI, A
通讯作者：
ZAGARI, A
影响因子：
3.5
作者：
APHANASENKO, GA;DUDKIN, SM;SEVERIN, ES
通讯作者：
SEVERIN, ES