Reactive Oxygen Species: A Breath of Life or Death?

Abstract

New insights into cancer cell^specific biological pathways are urgently needed to promote development of rationally targeted therapeutics. Reactive oxygen species (ROS) and their role in cancer cell response to growth factor signaling and hypoxia are emerging as verdant areas of exploration on the road to discovering cancer's Achilles heel. One of the distinguishing and nearuniversal hallmarks of cancer growth is hypoxia. Unregulated cellular proliferation leads to formation of cellular masses that extend beyond the resting vasculature, resulting in oxygen and nutrient deprivation. The resulting hypoxia triggers a number of critical adaptations that enable cancer cell survival, including apoptosis suppression, altered glucose metabolism, and an angiogenic phenotype. Ironically, recent investigations suggest that oxygen depletion stimulates mitochondria to elaborate increased ROS, with subsequent activation of signaling pathways, such as hypoxia inducible factor 1a, that promote cancer cell survival and tumor growth. Because mitochondria are key organelles involved in chemotherapy-induced apoptosis induction, the relationship between mitochondria, ROS signaling, and activation of survival pathways under hypoxic conditions has been the subject of increased study. Insights into mechanisms involved in ROS signaling may offer novel avenues to facilitate discovery of cancer-specific therapies. Preclinical and clinical evaluation of agents that modify ROS signaling in cancer offers a novel avenue for intervention. This review will cover recent work in ROS-mediated signaling in cancer cells and its potential as a target for developmental therapeutics.

Protein cysteine sulfinic acid reductase (sulfiredoxin) as a regulator of cell proliferation and drug response

“…The relevance of the elevated p21 is less clear, but is discussed below in more detail. The relevance of cellular redox balance in determining response to certain chemotherapeutic drugs has been well documented (Fruehauf and Meyskens, 2007). Lung cancer is therapeutically managed with cisplatin (NCI Cancer Bulletin 4(19), 2007).…”

Many forks in the path: cycling with FoxO

“…Indeed, most chemotherapeutic drugs are reported to arrest or delay cell cycle progression, and if the DNA damage or other cellular defects are extensive, the cell will undergo either apoptosis or cellular senescence (Lukas et al, 2004;Bartkova et al, 2005). Moreover, cancer cells may be considered to display an enhanced or higher level of basal stress, such as increased levels of reactive oxygen species or stress kinase activity, and it is precisely the deregulation of cell cycle checkpoints that allow cancer cells to tolerate such cellular conditions, while simultaneously promoting genomic instability and tumour progression (Giles, 2006;Wu, 2006;Fruehauf and Meyskens, 2007). One such mechanism by which cancer cells can tolerate cellular stress is the deactivation of FoxO3a, which would be anticipated to be activated by oxidative stress and stress kinases, both of which may converge through c-Jun N-terminal kinase-mediated phosphorylation of FoxO3a (Essers et al, 2004(Essers et al, , 2005Vogt et al, 2005;Huang and Tindall, 2007).…”

Expression of myeloperoxidase enhances the chemosensitivity of leukemia cells through the generation of reactive oxygen species and the nitration of protein

“…6,7 ROS are known to modulate the regulators of a wide variety of cellular biological processes including calcium signaling, protein phosphorylation, gene expression, cell growth and differentiation, and chemotaxis. 8,9 They also induce cellular damage associated with lipid peroxidation and alteration of proteins and nucleic acids. 10 Mainly on the basis of in vitro studies, it is believed that ROS produced by chemotherapeutic agents play a role in the induction of apoptosis in target cells, which could directly relate to the efficacy of chemotherapy.…”