Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis
Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis
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DOI：
10.1007/s00109-017-1590-9
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发表时间：
2017-12-01
影响因子：
4.7
通讯作者：
Calorini, Lido
中科院分区：
文献类型：
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作者：
Andreucci, Elena;Peppicelli, Silvia;Calorini, Lido
在能够促进耐药性和侵袭性表型的癌细胞的适应性反应的参与者中，碳酸酐酶IX（CAIX）最近已成为最相关的药物靶标之一。事实上，CAIX靶向已经引起了很大的兴趣，选择性抑制剂目前正在进行临床试验。缺氧已被确定为CAIX的主要诱导因子，但迄今为止，很少有人知道肿瘤微环境的另一个重要特征，即，细胞外酸中毒，对CAIX表达和活性产生影响。在过去的几十年里，酸性微环境已被认为与侵袭性肿瘤表型相关，这些表型具有上皮向间质转化（EMT）特征、高侵袭和迁移能力、凋亡和耐药性。我们证明，与在标准条件（pH 7.4 +/-0.1）下生长的细胞相比，短暂和长期暴露于酸化培养基（pH 6.7 +/-0.1）的黑色素瘤、乳腺癌和结直肠癌细胞显示出显著增加的CAIX表达。此外，我们观察到CAIX抑制剂FC 16 - 670 A（也称为SLC-0111，其刚刚成功结束I期临床试验）不仅在酸中毒下防止这种表达增加，而且仅在酸化的癌细胞中促进凋亡和坏死程序。因此，CAIX可以代表酸性癌细胞的选择性靶点，并且FC 16 - 670 A抑制剂可以作为影响这种以常规治疗逃避为特征的侵袭性亚群的有用工具。
Among the players of the adaptive response of cancer cells able to promote a resistant and aggressive phenotype, carbonic anhydrase IX (CAIX) recently has emerged as one of the most relevant drug targets. Indeed, CAIX targeting has received a lot of interest, and selective inhibitors are currently under clinical trials. Hypoxia has been identified as the master inductor of CAIX, but, to date, very few is known about the influence that another important characteristic of tumor microenvironment, i.e., extracellular acidosis, exerts on CAIX expression and activity. In the last decades, acidic microenvironment has been associated with aggressive tumor phenotype endowed with epithelial-to-mesenchymal transition (EMT) profile, high invasive and migratory ability, apoptosis, and drug resistance. We demonstrated that melanoma, breast, and colorectal cancer cells transiently and chronically exposed to acidified medium (pH 6.7 +/- 0.1) showed a significantly increased CAIX expression compared to those grown in standard conditions (pH 7.4 +/- 0.1). Moreover, we observed that the CAIX inhibitor FC16-670A (also named SLC-0111, which just successfully ended phase I clinical trials) not only prevents such increased expression under acidosis but also promotes apoptotic and necrotic programs only in acidified cancer cells. Thus, CAIX could represent a selective target of acidic cancer cells and FC16-670A inhibitor as a useful tool to affect this aggressive subpopulation characterized by conventional therapy escape.