Redox catalysts as sensitisers towards oxidative stress

Abstract

The predominance of oxidative stress in many tumour cell environments provides a means to selectively target these cells via protein oxidation. The zinc ¢ngers of transcription factors utilise cysteine thiols for structural zinc coordination. Redox control of DNA binding regulates transcription and therefore the overall rates of proliferation, apoptosis and necrosis in the carcinoma. We report here the adverse e¡ects of glutathione peroxidase (GPx) mimics towards zinc ¢nger motifs and PC12 cell survival. Nanomolar catalyst concentrations facilitated H 2 O 2 -induced oxidation of an Sp1 transcription factor fragment. In PC12 cells GPx catalysis triggered a signi¢cant increase in cell death, correlating with severity of oxidative stress. As a consequence, we conclude that GPx mimics are potential chemotherapeutic agents. ß

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…Experimental therapeutics that can undergo spontaneous or enzyme-driven redoxcycling with production of cytotoxic organic free radicals and ROS can target cancer cells through selective induction of oxidative stress as reviewed extensively elsewhere (120,237,379). As prooxidant catalysts, redox cyclers mediate electron transfer from a cellular reducing agent [e.g., glutathione or NAD(P)H] onto oxygen with production of ROS (120,128,237,358,379). After electron transfer to oxygen, the redox catalyst is regenerated by spontaneous or enzyme-driven reduction.…”

“…[1,4]naphthoquinone. Recently, drug development of multifunctional redox catalysts that selectively enhance oxidative stress in cancer cells through glutathione depletion, ROS formation, and thioloxidation of crucial redox target proteins including transcription factors has been initiated (120,128). These redox catalysts, active in the nanomolar range, display both redox features of quinone-based cyclers and small molecule chalcogen-based glutathione peroxidase mimetics.…”

“…Consequently, pro-oxidant and antioxidant redox effects are achieved as a function of cellular redox status and glutathione availability, providing a therapeutic window based on cancer cell redox dysregulation with elevated cellular peroxide and decreased glutathione levels. The promiscuous peroxidase activity of the organochalcogen moiety may result in depletion of cellular thiols and can also lead to oxidative disruption of redox-sensitive zinc finger transcription factors including Sp1 observed with prototype agents including 4,4 0 -dihydroxydiphenyl telluride as discussed in Section III.G (128). The potential therapeutic usefulness of these promising experimental redox catalysts with transparent SAR active in cell culture models awaits further validation in stringent preclinical in vivo models.…”

“…For example, electrochemical analysis of the Sp1 zinc finger by cyclic voltammetry revealed a redox potential that thermodynamically favors preferential oxidative disruption of this particular thiol target by redox cycler prototype organochalcogens in oxidatively stressed cells with lowered glutathione content (128). In analogy, computational analysis of steric and electrostatic screening parameters in zinc finger cores revealed the preferential redox vulnerability of the estrogen receptor C-terminal zinc finger that was disrupted through electrophilic zinc ejection by prototype agents, including DIBA and BITA (361).…”

“…The combined evidence provided by multiple studies on (a) antiviral intervention targeting zinc finger domains in viral oncogenic proteins (23), (b) Sp1 zinc finger inactivation in oxidatively stressed cells by prooxidant glutathione peroxidase mimetics (128) and (c) pharmacological disruption of the ER DNA-binding domain by small molecule prooxidant modification of the ER zinc finger (360, 361) strongly suggests feasibility of disrupting oncogenic transcriptional control through redox-based inactivation of specific DNA-binding zinc fingers. Further research will determine if these early reports may herald a new era of nongenotoxic redox chemotherapeutics that selectively target nuclear hormone receptors and other transcription factors.…”