An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo
| Autor: | Arnaldo Parra Damas, Bettina von Neubeck, Reinhard Zeidler, Hagen Scherb, Chiara Riganti, Gabor Gondi, Ali Ertürk, Chenchen Pan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Lung Neoplasms medicine.drug_class 6A10 antibody CAXII P-glycoprotein chemoresistance Breast Neoplasms Monoclonal antibody 03 medical and health sciences Mice 0302 clinical medicine Breast cancer In vivo Cell Line Tumor medicine Animals Humans Doxorubicin ATP Binding Cassette Transporter Subfamily B Member 1 Antibodies Blocking Carbonic Anhydrases Cell Proliferation biology Chemistry Antibodies Monoclonal medicine.disease In vitro 030104 developmental biology 6a10 Antibody Caxii Chemoresistance Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Female medicine.drug |
| Zdroj: | Int. J. Cancer 143, 2065-2075 (2018) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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