Pharmacological modulation of reactive oxygen species in cancer treatment.
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.
Judit
J
Ribas
Paolo
P
Mattiolo
Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida / IRB Lleida, Edifici de Biomedicina 1, Av. Rovira Roure 80, 25198-Lleida, Catalunya, Spain. jacint.boix@mex.udl.cat.
Jacint
J
Boix
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C545747:2-phenylacetylenesulfonamide; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019328:Buthionine Sulfoximine