This research has been published online in the Journal of Cellular Physiology.
Malignant mesothelioma is the rare form of cancer related to lungs caused by asbestos. Mito-carboxy-proxyl is a mitochondria-targeted nitroxide inhibiting peroxide-induced oxidative stress. TEMPOL are made up of piperidine nitroxides and they mostly used as antioxidants. Mito-TEMPOL is the derivative of TEMPOL that are designed to target oxidants while protecting mitochondria.
Researchers have found that both Mito-carboxy-proxyl and Mito-TEMPOL inhibits FOXM1 expression and malignant mesothelial cell viability through stimulation of redox homeostasis that has been resulted from the disruption of the mitochondrial architecture. FOXM1 is a redox-responsive transcription factor that is found to be the significant therapeutic target in solid malignancies.
You can read the abstract of the paper here,
Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM.
Brian Cunniff, Kira Benson, Jason Stumpff, Kheng Newick, Paul Held, Douglas Taatjes, Joy Joseph, Balaraman Kalyanaraman, Nicholas H. Heintz, (2012). Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells. Journal of Cellular Physiology, DOI: 10.1002/jcp.24232