Pharmacological Modulation of Reactive Oxygen Species in Cancer Treatment
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Aerobic metabolism of mammalian cells leads to the generation of reactive oxygen species (ROS). To cope with this toxicity, evolution provided cells with effective antioxidant systems like glutathione. Current anticancer therapies focus on the cancer dependence on oncogenes and non-oncogenes. Tumors trigger mechanisms to circumvent the oncogenic stress and to escape cell death. In this context we have studied 2-phenylethinesulfoxamine (PES), which disables the cell protective mechanisms to confront the proteotoxicity of damaged and unfolded proteins. Proteotoxic stress is increased in tumor cells, thus providing an explanation for the anticancer selectivity of PES. In addition, we have found that PES induces a severe oxidative stress and the activation of p53. The reduction of the cell content in glutathione by means of L-buthionine-sulfoximine (BSO) synergizes with PES. In conclusion, we have found that ROS constitutes a central element in a series of positive feed-back loops in the cell. ROS, p53, proteotoxicity, autophagy and mitochondrial dynamics are interconnected with the mechanisms leading to cell death, either apoptotic or necrotic. This network of interactions provides multiple targets for drug discovery and development in cancer.
Is part ofCurrent Drug Targets, 2015, vol. 16, num. 1, p. 31-37
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Mattiolo, Paolo; Barbero-Farran A.; Yuste Mateos, Víctor J. (Víctor José); Boix Torras, Jacint; Ribas i Fortuny, Judit (Elsevier, 2014)2-Phenylethynesulfonamide (PES) or pifithrin-μ is a promising anticancer agent with preferential toxicity for cancer cells. The type of cell death and the molecular cascades activated by this compound are controversial. ...
Mattiolo, Paolo; Barbero-Farran A.; Amigó J.; Ripamonti M.; Ribas i Fortuny, Judit; Boix Torras, Jacint (Elsevier, 2014)PES (2-phenylethynesulfonamide) was initially identified as an inhibitor of p53 translocation to mitochondria and named Pifithrin-µ. Further studies showed that PES selectively killed tumour cells and was thus a promising ...
Mattiolo, Paolo; Yuste Mateos, Víctor J. (Víctor José); Boix Torras, Jacint; Ribas i Fortuny, Judit (Elsevier, 2015-12)Autophagy is generally regarded as a mechanism to promote cell survival. However, autophagy can occasionally be the mechanism responsible of cell demise. We have found that a concomitant depletion of glucose, nutrients and ...