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 antitumour activity in vitro, it is thought that the enzyme is mandatory for maximum tumour 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 tumour 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. This article is protected by copyright. All rights reserved.

An inhibitory antibody targeting Carbonic Anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo

Riganti, Chiara;
2018-01-01

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 antitumour activity in vitro, it is thought that the enzyme is mandatory for maximum tumour 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 tumour 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. This article is protected by copyright. All rights reserved.
2018
143
8
2065
2075
6A10 antibody; CAXII; P-glycoprotein; chemoresistance
von Neubeck, Bettina; Gondi, Gabor; Riganti, Chiara; Pan, Chenchen; Parra Damas, Arnaldo; Scherb, Hagen; Ertürk, Ali; Zeidler, Reinhard
File in questo prodotto:
File Dimensione Formato  
von Neubeck, preprint IJC 2018.pdf

Accesso aperto

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 4.9 MB
Formato Adobe PDF
4.9 MB Adobe PDF Visualizza/Apri
von Neubeck, IJC MS and Supporting, 2018.pdf

Accesso riservato

Descrizione: von Neubeck, MS and Supporting Information, 2018
Tipo di file: PDF EDITORIALE
Dimensione 1.79 MB
Formato Adobe PDF
1.79 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1670022
Citazioni
  • ???jsp.display-item.citation.pmc??? 24
  • Scopus 41
  • ???jsp.display-item.citation.isi??? 39
social impact