PG545, a Heparan Sulfate Mimetic, Reduces Heparanase Expression In Vivo, Blocks Spontaneous Metastases and Enhances Overall Survival in the 4T1 Breast Carcinoma Model
PG545, a Heparan Sulfate Mimetic, Reduces Heparanase Expression In Vivo, Blocks Spontaneous Metastases and Enhances Overall Survival in the 4T1 Breast Carcinoma Model
复制标题
DOI：
10.1371/journal.pone.0052175
复制
发表时间：
2012-12-26
期刊：
影响因子：
3.7
通讯作者：
Dredge, Keith
中科院分区：
文献类型：
--
作者：
Hammond, Edward;Brandt, Ralf;Dredge, Keith
PG545是一种临床相关的硫酸肝素（HS）模拟物，除了具有抗血管生成特性外，还可作为肝素酶抑制剂，其作用机制可能与已批准的血管生成抑制剂不同。肝素酶对HS的降解与细胞传播和转移过程密切相关。因此，PG545的抗转移活性与肝素酶的酶功能有关，肝素酶是已知的唯一能切割HS的内糖苷酶，是细胞外基质（ECM）的重要组成部分，代表了某些转移性癌症适应症的治疗干预的潜在途径。最近人们对临床相关转移的小鼠模型中缺乏总生存期作为终点的担忧促使我们在非手术和手术（乳房切除术）设置的4T1同基因乳腺癌模型中研究PG545对原发肿瘤生长和自发转移疾病进展的影响。PG545在治疗小鼠中显著抑制原发肿瘤生长，但重要的是也抑制肺转移，酪氨酸激酶抑制剂索拉非尼没有观察到这种作用。重要的是，与对照和索拉非尼组相比，PG545显著提高了总生存率，这表明PG545对肝素酶的抑制作用确实是诱导抗转移活性的关键因素。除了阻断肿瘤细胞中常见的血管生成信号通路外，PG545治疗还显著降低了原发性肿瘤和肺中肝素酶的表达。这些结果支持了PG545的持续发展，并强调了其在转移性疾病中的潜在效用。
PG545 is a clinically relevant heparan sulfate (HS) mimetic which, in addition to possessing anti-angiogenic properties, also acts as a heparanase inhibitor which may differentiate its mechanism(s) of action from approved angiogenesis inhibitors. The degradation of HS by heparanase has been strongly implicated in cell dissemination and the metastatic process. Thus, the anti-metastatic activity of PG545 has been linked to the enzymatic function of heparanase - the only endoglycosidase known to cleave HS, an important component of the extracellular matrix (ECM) which represents a potential avenue for therapeutic intervention for certain metastatic cancer indications. Recent concerns raised about the paucity of overall survival as an endpoint in mouse models of clinically relevant metastasis led us to examine the effect of PG545 on the progression of both primary tumor growth and the spontaneously metastasizing disease in the 4T1 syngeneic breast carcinoma model in a non-surgical and surgical (mastectomy) setting. PG545 significantly inhibited primary tumor growth but importantly also inhibited lung metastasis in treated mice, an effect not observed with the tyrosine kinase inhibitor sorafenib. Importantly, PG545 significantly enhanced overall survival compared to vehicle control and the sorafenib group, suggesting PG545's inhibitory effect on heparanase is indeed a critical attribute to induce anti-metastatic activity. In addition to blocking a common angiogenic signalling pathway in tumor cells, the expression of heparanase in the primary tumor and lung was also significantly reduced by PG545 treatment. These results support the ongoing development of PG545 and highlight the potential utility in metastatic disease settings.