Premium
Nuclear factor‐κB as a potential therapeutic target for the novel cytotoxic agent LC‐1 in acute myeloid leukaemia
Author(s) -
Jenkins Christopher,
Hewamana Saman,
Gilkes Amanda,
Neelakantan Sundar,
Crooks Peter,
Mills Ken,
Pepper Chris,
Burnett Alan
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2008.07392.x
Subject(s) - parthenolide , cytotoxic t cell , myeloid , pharmacology , cancer research , in vitro , immunology , medicine , apoptosis , biology , biochemistry
Summary Nuclear factor‐κB (NF‐κB) 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‐κB in human myeloid blasts and a clear correlation between NF‐κB expression and in vitro cytoprotection. High NF‐κB 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 μmol/l for AML cells, compared with 12·8 μmol/l for normal marrow cells. LC‐1 was shown to reduce the five individual human NF‐κB Rel proteins in a dose‐dependent manner. The subsequent inhibition of many NF‐κB‐regulated cytokines was also demonstrated. Importantly, sensitivity to LC‐1 was correlated with the basal NF‐κB activity. Consequently, LC‐1 treatment provides a proof of principle for the use of NF‐κB inhibitors in the treatment of AML.