Hypoxia plays a key role in
tumor progression and resistance to
radiotherapy. Expression of the transmembrane-tethered
enzyme carbonic anhydrase IX (CA IX) is strongly induced by
hypoxia. High CA IX expression levels correlate with poor prognosis in
cancer patients. Previously, we showed that the downregulation of CA IX expression by
siRNA interference and the inhibition of CA IX activity results in increased cytotoxicity, inhibition of migration and radiosensitization of hypoxic
cancer cells.
Betulinic acid (BA) is a natural compound derived from birch bark. It has shown promising anti-
tumor effects due to its
cancer cell specific cytotoxic properties. We have shown that BA inhibits the HIF-1α pathway, resulting in apoptosis, inhibition of migration and enhanced cytotoxicity of
breast cancer cells. In this study, we investigate the effects of the novel
betulin derivative 3-O-acetylbetulin (3-AC) and
carbonic anhydrase inhibitors (CAI) octyl disulfamate (OCT) or 4-(3-[4-fluorophenyl]ureido)
benzenesulfonamide (SLC-0111), on cellular and radiobiological parameters in MDA-MB-231 and MCF-7 cells. Treatment with 3-AC or OCT alone only caused moderate cytotoxicity, reduction in cell migration, ROS production and DNA damage. However, the combined treatment with 3-AC and CAI strongly enhanced radiosensitivity, increased cytotoxicity, inhibited cell motility and enhanced DNA damage. Our findings suggest that the combination of two bioactive drugs 3-AC and a CAI, such as OCT or
SLC-0111, could be a promising therapeutic approach for targeting hypoxic
tumor cells.