Coenzyme Q₁₀ as an Inhibitor of Effector Release from One-Electron-Reduced Bioreductive Anticancer Prodrugs

The kinetic parameters for the release of anticancer effectors from the radical anions of prodrugs through fragmentation have been measured under conditions that model the interfacial region where the enzymatic reduction in the prodrugs takes place. While the back-oxidation of the radical anions via O₂ mainly occurs under normoxia, preventing radical anion fragmentation, this is not the case for the lower concentrations of O₂ found in hypoxic regions of tumors. Rate-constant data show that O₂ concentrations known to bring about a 50% decrease in the level of cell kill arising from the prodrugs in anoxia (the K-value) do not significantly inhibit the fragmentation of radical anions. Evidence is put forward suggesting that radical anions can undergo an electron transfer to ubiquinone (CoQ₁₀, UQ) in competition with the fragmentation of the radical anions releasing effectors. The prior inhibition of the synthesis of UQ in cells is put forward as a possible approach to increase the effectiveness of such prodrugs in killing hypoxic tumor cells.