Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

Abstract

Cancer cells are vulnerable to reactive oxygen species (ROS) due to their abnormal redox environment. Accordingly, combination of chemotherapy and oxidative stress has gained increasing interest for the treatment of cancer. We report a novel seleno-prodrug of gemcitabine (<b>Gem</b>), <b>Se-Gem</b>, and evaluated its activation and biological effects in cancer cells. <b>Se-Gem</b> was prepared by introducing a 1,2-diselenolane (a five-membered cyclic diselenide) moiety into the parent drug <b>Gem</b> <i>via</i> a carbamate linker. <b>Se-Gem</b> is preferably activated by glutathione (GSH) and displays a remarkably higher potency than <b>Gem</b> (up to a 6-fold increase) to a panel of cancer cell lines. The activation of <b>Se-Gem</b> by GSH releases <b>Gem</b> and a seleno-intermediate nearly quantitatively. Unlike the most ignored side products in prodrug activation, the seleno-intermediate further catalyzes a conversion of GSH and oxygen to GSSG (oxidized GSH) and ROS <i>via</i> redox cycling reactions. Thus <b>Se-Gem</b> may be considered as a suicide agent to deplete GSH and works by a combination of chemotherapy and oxidative stress. This is the first case that employs a cyclic diselenide in prodrug design, and the success of <b>Se-Gem</b> as well as its well-defined action mechanism demonstrates that the 1,2-diselenolane moiety may serve as a general scaffold to advance constructing novel therapeutic molecules with improved potency <i>via</i> a combination of chemotherapy and oxidative stress.