Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia
Data(s) |
01/12/2008
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Resumo |
Nuclear factor-kappaB (NF-kappaB) has been implicated in a number of malignancies and has been suggested to be a potential molecular target in the treatment of leukaemia. This study demonstrated the constitutive activation of NF-kappaB in human myeloid blasts and a clear correlation between NF-kappaB expression and in vitro cytoprotection. High NF-kappaB expression was found in many of the poor prognostic acute myeloid leukaemia (AML) subtypes, such as French-American-British classification M0 and M7, and the poor cytogenetic risk group. The in vitro effects of LC-1, a novel dimethylamino-parthenolide analogue, were assessed in 62 primary untreated AML samples. LC-1 was found to be cytotoxic to AML cells in a dose-dependent manner, mediated through the induction of apoptosis. The median drug concentration necessary to kill 50% of the cells was 4.5 micromol/l for AML cells, compared with 12.8 micromol/l for normal marrow cells. LC-1 was shown to reduce the five individual human NF-kappaB Rel proteins in a dose-dependent manner. The subsequent inhibition of many NF-kappaB-regulated cytokines was also demonstrated. Importantly, sensitivity to LC-1 was correlated with the basal NF-kappaB activity. Consequently, LC-1 treatment provides a proof of principle for the use of NF-kappaB inhibitors in the treatment of AML. |
Identificador | |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
Jenkins , C , Hewamana , S , Gilkes , A , Neelakantan , S , Crooks , P , Mills , K , Pepper , C & Burnett , A 2008 , ' Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia ' British Journal of Haematology , vol 143 , no. 5 , pp. 661-71 . DOI: 10.1111/j.1365-2141.2008.07392.x |
Palavras-Chave | #/dk/atira/pure/subjectarea/asjc/2700/2720 #Hematology |
Tipo |
article |