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.
Keywords: Cell death, Cell experimental pharmacology, L-buthionine-sulfoximine, Mdivi-1, Oxidative stress, p53, 2-
phenylethinesulfoxamine, proteotoxic stress.
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