An Antioxidant Cocktail of tert-Butylhydroquinone and a Manganese Porphyrin Induces Toxic Levels of Oxidative Stress in Cancer Cells

Despite significant advancement in cancer treatments, therapies with minimal toxicity to healthy cells are still limited. One targetable weakness of cancer cells is their sensitivity to oxidative stress. We find that the combination of two antioxidants-the common food additive <i>tert</i>-butylhydroquinone (tBHQ) and a manganese porphyrin in clinical trials, MnTnBuOE-2-PyP⁵⁺ (MnBuOE)-increases oxidative stress and causes apoptotic death in several cancer cell lines, but not in mouse primary fibroblasts. Investigating the mechanism of cell death, MnBuOE is observed to catalyze the oxidation of tBHQ, producing the electrophilic quinone <i>tert</i>-butylquinone (tBQ). A critical role for tBQ and its electrophilic character was revealed with the observation that di-<i>tert</i>-butylhydroquinone (dtBHQ) in combination with MnBuOE causes no observable oxidative stress and is non-toxic, despite rapid oxidation to di-<i>tert</i>-butylquinone (dtBQ), a non-electrophilic quinone. Cell death from the combination of tBHQ and MnBuOE appears to be completely dependent on the generation of hydrogen peroxide, as shown by the inclusion of catalase. This system, in which two non-toxic molecules in combination cause specific toxicity to cancer cells, is a potential means to kill cancer cells in a targeted manner.