Koltai Tomas
Gerencia de Efectores Sanitarios Propios, Instituto Nacional de la Seguridad Social para Jubilados y Pensionados, Buenos Aires, República Argentina.
Onco Targets Ther. 2014 Mar 20;7:447-56. doi: 10.2147/OTT.S58622. eCollection 2014.
Clusterin is a heterodimeric disulfide-linked glycoprotein (449 amino acids) isolated in the rat prostate after castration. It is widely distributed in different tissues and highly conserved in species. There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis. Clusterin is implicated in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement cascade, representing a truly multifunctional protein. Isoform 2 is overexpressed under cellular stress conditions and protects cells from apoptosis by impeding Bax actions on the mitochondrial membrane and exerts other protumor activities, like phosphatidylinositol 3-kinase/protein kinase B pathway activation, modulation of extracellular signal-regulated kinase 1/2 signaling and matrix metallopeptidase-9 expression, increased angiogenesis, modulation of the nuclear factor kappa B pathway, among others. Its overexpression should be considered as a nonspecific cellular response to a wide variety of tissue insults like cytotoxic chemotherapy, radiation, excess of free oxygen radicals, androgen or estrogen deprivation, etc. A review of the recent literature strongly suggests potential roles for custirsen in particular, and proapoptosis treatments in general, as novel modalities in cancer management. Inhibition of clusterin is known to increase the cytotoxic effects of chemotherapeutic agents, and custirsen, a second-generation antisense oligonucleotide that blocks clusterin, is being tested in a Phase III clinical trial after successful results were achieved in Phase II studies. A major issue in cancer evolution that remains unanswered is whether clusterin represents a driving force of tumorigenesis or a late phenomenon after chemotherapy. This review presents preclinical data that encourages trials in various types of cancer other than advanced castration-resistance prostate cancer and discusses briefly the appropriate timing for clusterin inhibition in the clinical context.
簇集素是一种异源二聚体的二硫键连接糖蛋白（449个氨基酸），在大鼠去势后的前列腺中分离得到。它广泛分布于不同组织，在物种间高度保守。有两种亚型（1和2），在细胞凋亡方面具有拮抗作用。簇集素参与多种生物学过程，包括脂质转运、膜循环利用、细胞黏附、程序性细胞死亡和补体级联反应，是一种真正的多功能蛋白。亚型2在细胞应激条件下过度表达，通过阻碍 Bax 在线粒体膜上的作用来保护细胞免于凋亡，并发挥其他促肿瘤活性，如磷脂酰肌醇3激酶/蛋白激酶B通路激活、细胞外信号调节激酶1/2信号传导和基质金属肽酶-9表达的调节、血管生成增加、核因子κB通路调节等。其过度表达应被视为对多种组织损伤的非特异性细胞反应，如细胞毒性化疗、辐射、过量的氧自由基、雄激素或雌激素剥夺等。对近期文献的综述强烈表明，特别是custirsen以及一般的促凋亡治疗作为癌症管理的新方式具有潜在作用。已知抑制簇集素可增加化疗药物的细胞毒性作用，custirsen是一种第二代反义寡核苷酸，可阻断簇集素，在II期研究取得成功结果后，正在进行III期临床试验。癌症演变中一个尚未得到解答的主要问题是簇集素是代表肿瘤发生的驱动力还是化疗后的晚期现象。本综述提供了临床前数据，鼓励在除晚期去势抵抗性前列腺癌之外的各种癌症中进行试验，并简要讨论了临床背景下抑制簇集素的合适时机。
