Impact of mitochondrial superoxide dismutase (MnSOD) on cytotoxic activity of resveratrol and its hydroxylated analogues in HeLa and C33A cancer cell lines

The naturally occurring polyphenol resveratrol (3,4′,5‐trihydroxy‐stilbene, 3,4′,5‐HS, RES) was shown as chemopreventive and proapototic agent. RES also undergoes monohydroxylation by CYP1B1 to form 3,3′,4′,5‐HS and 3,4,4′,5‐HS, metabolites with higher anticancer activity and stronger antioxidant properties. It was therefore hypothesized that RES analogues (RA) possessing more then 3 hydroxyl groups may act stronger against cancer cells than RES. In order to investigate a structure‐activity relationship between pro/antioxidant properties and cytotoxicity, the following RA with at least 2 phenolic groups in neighborhood: 3,3′,4′,5‐HS, 3,3′,4,4′,5,5′‐HS and the compounds without such a structure: RES and 3,3′,5,5′‐HS, were synthesized. It was previously shown by our group that the cytotoxiciy of RA correlates with the formation of antioxidant‐derived prooxidants when at least two hydroxyl groups are present in neighboring positions forming as a result of their redox‐cycling superoxide radical. In the present work we tested this hypothesis in cell culture system using HeLa and C33A cancer cell lines. It was shown that MnSOD overexpressing HeLa cells are much more resistant to superoxide generating RA than C33A cells.