title: Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells.
abstract: Betulinic acid (BA), a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA), such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8-2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC50 values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC50 values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1) and 1.75 (CAI 3) under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer.
authors.affiliation: Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany. matthias.bache@medizin.uni-halle.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bache
authors.affiliation: Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany. muench.christin@web.de.
authors.forename: Christin
authors.initials: C
authors.lastname: Münch
authors.affiliation: Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany. antje.hahnel@uk-halle.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Güttler
authors.affiliation: Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany. henri.wichmann@uk-halle.de.
authors.forename: Henri
authors.initials: H
authors.lastname: Wichmann
authors.affiliation: Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany. katharina.theuerkorn@uk-halle.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Theuerkorn
authors.affiliation: Biozentrum, Martin Luther Universität Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany. daniel.emmerich@student.uni-halle.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Emmerich
authors.affiliation: Biozentrum, Martin Luther Universität Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany. reinhard.paschke@biozentrum.uni-halle.de.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Paschke
authors.affiliation: Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany. dirk.vordermark@medizin.uni-halle.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Vordermark
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013451:Sulfonic Acids / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D011838:Radiation-Sensitizing Agents; D013451:Sulfonic Acids; C005741:sulfamic acid
keywords: betulinic acid derivatives; breast cancer; carbonic anhydrase inhibitors; cytotoxicity; hypoxia; irradiation; normoxia