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.