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一种针对碳酸酐酶 XII 的抑制性抗体可消除化学耐药性,并在体内原位乳腺癌模型中显著减少肺转移。

An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo.

机构信息

Department of Gene Vectors, Helmholtz Center for Environmental Health, Munich, Germany.

Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.

出版信息

Int J Cancer. 2018 Oct 15;143(8):2065-2075. doi: 10.1002/ijc.31607. Epub 2018 Aug 10.

DOI:10.1002/ijc.31607
PMID:29786141
Abstract

Carbonic anhydrase XII (CAXII) is a membrane-tethered ectoenzyme involved in intracellular pH regulation and overexpressed across various types of human cancer. Because CAXII inhibition shows antitumor activity in vitro, it is thought that the enzyme is mandatory for maximum tumor growth, above all under hypoxic conditions. Recently, it has been shown that CAXII is co-expressed along with the P-glycoprotein (P-GP) on many tumor cells and that both proteins physically interact. Of interest, blocking CAXII activity also decreases P-GP activity in cancer cells both in vitro and in vivo. Previously, we have reported on the development of a monoclonal antibody, termed 6A10, which specifically and efficiently blocks human CAXII activity. Here, we demonstrate that 6A10 also indirectly reduces P-GP activity in CAXII/P-GP double-positive chemoresistant cancer cells, resulting in enhanced chemosensitivity as revealed by enhanced accumulation of anthracyclines and increased cell death in vitro. Even more important, we show that mice carrying human triple-negative breast cancer xenografts co-treated with doxorubicin (DOX) and 6A10 show a significantly reduced number of metastases. Collectively, our data provide evidence that the inhibition of CAXII with 6A10 is an attractive way to reduce chemoresistance of cancer cells and to interfere with the metastatic process in a clinical setting.

摘要

碳酸酐酶 XII(CAXII)是一种膜结合的外切酶,参与细胞内 pH 调节,在各种类型的人类癌症中过表达。由于 CAXII 抑制在体外显示出抗肿瘤活性,因此人们认为该酶对于最大肿瘤生长是必需的,尤其是在缺氧条件下。最近,已经表明 CAXII 与许多肿瘤细胞上的 P-糖蛋白(P-GP)共同表达,并且这两种蛋白质物理相互作用。有趣的是,阻断 CAXII 活性也会降低癌细胞中 P-GP 的活性,无论是在体外还是体内。先前,我们已经报道了开发一种单克隆抗体,称为 6A10,它特异性和有效地阻断人 CAXII 活性。在这里,我们证明 6A10 还可以间接降低 CAXII/P-GP 双阳性化学抗性癌细胞中的 P-GP 活性,从而增强化学敏感性,如蒽环类药物积累增加和体外细胞死亡增加所揭示的那样。更重要的是,我们表明,携带人三阴性乳腺癌异种移植物的小鼠同时接受多柔比星(DOX)和 6A10 治疗显示出转移数量显著减少。总的来说,我们的数据提供了证据,表明用 6A10 抑制 CAXII 是减少癌细胞化疗耐药性和在临床环境中干扰转移过程的一种有吸引力的方法。

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An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo.一种针对碳酸酐酶 XII 的抑制性抗体可消除化学耐药性,并在体内原位乳腺癌模型中显著减少肺转移。
Int J Cancer. 2018 Oct 15;143(8):2065-2075. doi: 10.1002/ijc.31607. Epub 2018 Aug 10.
2
P-glycoprotein-mediated chemoresistance is reversed by carbonic anhydrase XII inhibitors.碳酸酐酶XII抑制剂可逆转P-糖蛋白介导的化疗耐药性。
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Carbonic anhydrase XII expression is linked to suppression of Sonic hedgehog ligand expression in triple negative breast cancer cells.碳酸酐酶 XII 的表达与三阴性乳腺癌细胞中 Sonic hedgehog 配体表达的抑制有关。
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Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor.
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Cancer Cell Int. 2022 Nov 24;22(1):368. doi: 10.1186/s12935-022-02786-6.
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