title: The Sulfamate Small Molecule CAIX Inhibitor S4 Modulates Doxorubicin Efficacy.
abstract: Carbonic anhydrase IX (CAIX) is a tumor-specific protein that is upregulated during hypoxic conditions where it is involved in maintaining the pH balance. CAIX causes extracellular acidification, thereby limiting the uptake of weak basic chemotherapeutic agents, such as doxorubicin, and decreasing its efficacy. The aim of this study was to determine if doxorubicin efficacy can be increased when combined with the selective sulfamate CAIX inhibitor S4. The effect of S4 on doxorubicin efficacy was tested in vitro using cell viability assays with MDA-MB-231, FaDu, HT29 -CAIX high and HT29 -CAIX low cell lines. In addition, the efficacy of this combination therapy was investigated in tumor xenografts of the same cell lines. The addition of S4 in vitro increased the efficacy of doxorubicin in the MDA-MB-231 during hypoxic exposure (IC50 is 0.25 versus 0.14 µM, p = 0.0003). Similar results were observed for HT29-CAIX high with S4 during normoxia (IC50 is 0.20 versus 0.08 µM, p<0.0001) and in the HT29 -CAIX low cells (IC50 is 0.09 µM, p<0.0001). In vivo doxorubicin treatment was only effective in the MDA-MB-231 xenografts, but the efficacy of doxorubicin was decreased when combined with S4. In conclusion, the efficacy of doxorubicin treatment can be increased when combined with the selective sulfamate CAIX inhibitor S4 in vitro in certain cell lines. Nevertheless, in xenografts S4 did not enhance doxorubicin efficacy in the FaDu and HT29 tumor models and decreased doxorubicin efficacy in the MDA-MB-231 tumor model. These results stress the importance of better understanding the role of CAIX inhibitors in intratumoral pH regulation before combining them with standard treatment modalities, such as doxorubicin.
authors: Department of Radiation Oncology (MAASTRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Simon J A
authors: SJ
authors: van Kuijk
authors: Hypoxia and Therapeutics Group, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom.
authors: Roben G
authors: RG
authors: Gieling
authors: Department of Radiation Oncology (MAASTRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Raymon
authors: R
authors: Niemans
authors: Department of Radiation Oncology (MAASTRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Natasja G
authors: NG
authors: Lieuwes
authors: Department of Radiation Oncology (MAASTRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Rianne
authors: R
authors: Biemans
authors: Hypoxia and Therapeutics Group, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom.
authors: Brian A
authors: BA
authors: Telfer
authors: Department of Toxicology, NUTRIM-School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.
authors: Guido R M M
authors: GR
authors: Haenen
authors: Department of Radiation Oncology (MAASTRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Ala
authors: A
authors: Yaromina
authors: Department of Radiation Oncology (MAASTRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Philippe
authors: P
authors: Lambin
authors: Department of Radiation Oncology (MAASTRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Ludwig J
authors: LJ
authors: Dubois
authors: Hypoxia and Therapeutics Group, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom.
authors: Kaye J
authors: KJ
authors: Williams
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C575288:4-(3'-(3',5'-dimethylphenyl)ureido)phenyl sulfamate; D000903:Antibiotics, Antineoplastic; D002257:Carbonic Anhydrase Inhibitors; D010671:Phenylurea Compounds; D013449:Sulfonamides; D004317:Doxorubicin; D000071231:Carbonic Anhydrase IX