Zinc Influences the Efficacy of Betulinic Acid Treatment and Radiotherapy in Breast Cancer Cells

The trace element zinc influences a number of biological reactions, including cell growth, apoptosis, and DNA damage, which affect tumor therapy. The natural compound betulinic acid (BA) and its derivatives are known for their antiviral, antibacterial, and antitumor effects. Previous studies show that BA and 3-acetyl-28-sulfamoyloxybetulin (CAI3) have high cytotoxicity and induce radiosensitization in breast cancer cells. This study investigates the effects of zinc supplementation on treatment with BA or CAI3 and radiotherapy of breast cancer cell lines MDA-MB-231 and HS578T. Expression analysis shows that BA and CAI3 lead to altered expression of genes involved in zinc metabolism. Zinc supplementation affects cell survival and cell death alone and in combination with BA or CAI3 in both breast cancer cell lines. In MDA-MB-231 cells, zinc excess protects against ROS formation by BA or CAI3 and exhibits radioprotective effects compared to the single agent treatment. In contrast, in HS578T cells, zinc induces ROS formation but does not affect radiosensitivity. The variable effects of zinc on radiosensitivity highlight the importance of individualized treatment approaches. Although zinc has cytotoxic, pro-apoptotic, and anti-clonogenic effects, it seems worthwhile to consider its radioprotective properties when making treatment decisions in the case of adjuvant radiotherapy of breast cancer.