Peroxovanadium complexes have been identified as potent insulin mimetic agents and thus have been proposed for the treatment of diabetes. However, due to their nonselective inhibition of protein tyrosine phosphatases, these complexes affect a number of intracellular signaling pathways, both related and unrelated to insulin mimesis, jeopardizing their potential use as therapeutic agents. / Cytotoxic effects of three monoperoxovanadium complexes were studied with the hopes of establishing rules for determining cytotoxicity. MpV[pic] and mpV[dpc] displayed similar toxicity profiles and lead to the activation of members of the Mitogen Activated Protein Kinases (MAPK) superfamily in a dose- and time-dependent manner. On the other hand, mpV[NTA] appeared less toxic than the other two complexes studied, and accordingly, lead to a lower level, if at all, of MAPK phosphorylation. These results, although not conclusive, imply the participation of MAPKs in cell death. Cell death caused by these complexes presented features of both necrosis and apoptosis. / The second objective of this research was to further characterize the modulation of the ERK signaling cascade by the most commonly used peroxovanadium complex, bpV[phen] in a variety of different cellular contexts. It was discovered that signaling through a receptor with tyrosine kinase activity (RTK) coupled with cellular differentiation, as exemplified by the use of NGF and FGF, leads to ERK phosphorylation by 10 muM bpV[phen] for 1 hour that can be almost completely abolished by use of PD98059, an inhibitor of MEK. In contrast, non-differentiated cells, cells differentiated with a cyclic AMP analogue and PC12 cells treated with EGF appear to signal mostly through a non-PD98059-inhibitable pathway, when stimulated with the same dose of bpV[phen] for one hour.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.29912 |
| Date | January 1999 |
| Creators | Morinville, Anne. |
| Contributors | Maysinger, D. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001681907, proquestno: MQ55080, Theses scanned by UMI/ProQuest. |
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