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Potential Therapeutic Targets in Drug-Resistant CML .
Kabíčková, Tereza ; Toman, Ondřej (advisor) ; Klener, Pavel (referee)
The therapy of common haematological malignancy chronic myeloid leukaemia (CML) has dramatically improved patient prognosis upon approval of selective tyrosine kinase inhibitor (TKI) imanitib. However, subset of patients develops resistance to imanitib, which limits its therapeutic potential. We derived imatinib resistant CML-T1 human cell line by a long term increase of imatinib concentration in growth media. We have compared the protein expression profiles of the imatinib resistant and imatinib sensitive CML-T1 cells using proteomic analysis by 2DE. We have identified 11 differentially expressed proteins in the resistant cell line by MALDI MS. Na+ /H+ exchange regulatory cofactor (NHERF1) was significantly upregulated in the resistant cells, as confirmed by western blotting. Protein NHERF1 contains interactive binding domains known to be involved in regulation of Wnt signaling. We have uncovered dysregulation in expression levels of proteins involved in Wnt signaling in resistant CML-T1 cells, such as upregulation of Dishevelled 3 (Dvl3) and downregulation of transcription factor NFAT. Phosphatase calcineurin activates NFAT by dephosphorylation, causing subsequential NFAT translocation to the nucleus. We have considered this cellular event as a weak spot in the metabolism of the resistant cells,...
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Effect of iron overload on the induction of apoptosis in mammalian cells
Kabíčková, Tereza ; Balušíková, Kamila (advisor) ; Klíma, Martin (referee)
Iron cations are an important metal ions required to number of essential cell functions. On the other hand, ferrous iron can be very toxic as well. When surplus iron is present in cells, it can catalyze the formation of reactive oxygen species (especially hydroxyl radicals) by Fenton reaction. Iron homeostasis is predominantly regulated by very strict mechanisms on the level of iron uptake into the body. Moreover, iron absorption, transport and storage within the body can be also regulated using complex mechanisms which differ on the level of individual cells and on the level of whole organism. Deregulation of iron homeostasis causing an iron overload and generation of reactive oxygen radicals can evoke serious cell damage leading up to apoptotic cell death. Excess iron storage and subsequent development of oxidative stress can affect lot of different tissues in the body. The organ damages such as fibrosis, cirrhosis, hepatocellular carcinoma, heart failure, loss of β cells and glucose intolerance or diabetes mellitus in patients with iron overload are very often seen. Nevertheless, the apoptosis induced by iron overload has not been well elucidated yet. There are no complex informations about the precise mechanism by which oxidative stress affects different cell types or whether there are other...
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