Anti-Cancer Agents in Medicinal Chemistry

(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Michelle Prudhomme  
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France

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Redox-Active Quinones and Ascorbate: An Innovative Cancer Therapy That Exploits the Vulnerability of Cancer Cells to Oxidative Stress

Author(s): Julien Verrax, Raphael Beck, Nicolas Dejeans, Christophe Glorieux, Brice Sid, Rozangela C. Pedrosa, Julio Benites, David Vasquez, Jaime A. Valderrama, Pedro Buc Calderon.

Abstract:

Cancer cells are particularly vulnerable to treatments impairing redox homeostasis. Reactive oxygen species (ROS) can indeed play an important role in the initiation and progression of cancer, and advanced stage tumors frequently exhibit high basal levels of ROS that stimulate cell proliferation and promote genetic instability. In addition, an inverse correlation between histological grade and antioxidant enzyme activities is frequently observed in human tumors, further supporting the existence of a redox dysregulation in cancer cells. This biochemical property can be exploited by using redox-modulating compounds, which represent an interesting approach to induce cancer cell death. Thus, we have developed a new strategy based on the use of pharmacologic concentrations of ascorbate and redox-active quinones. Ascorbate-driven quinone redox cycling leads to ROS formation and provokes an oxidative stress that preferentially kills cancer cells and spares healthy tissues. Cancer cell death occurs through necrosis and the underlying mechanism implies an energetic impairment (ATP depletion) that is likely due to glycolysis inhibition. Additional mechanisms that participate to cell death include calcium equilibrium impairment and oxidative cleavage of protein chaperone Hsp90. Given the low systemic toxicity of ascorbate and the impairment of crucial survival pathways when associated with redox-active quinones, these combinations could represent an original approach that could be combined to standard cancer therapy.

Keywords: Ascorbate, cancer, quinone, redox cycling, oxidative stress, genetic instability, superoxide dismutase, glutathione (GSH), glucose transporters, ROS, NADPH-dependent selenoenzyme, ascorbate/menadione combination, asparaginase, intercalating agents, Ascorbate-driven quinone redox cycling leads

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Article Details

VOLUME: 11
ISSUE: 2
Year: 2011
Page: [213 - 221]
Pages: 9
DOI: 10.2174/187152011795255902
Price: $58