Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia.

Nuclear factor-kappa B (NF-kappa B) 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-kappa B in human myeloid blasts and a clear correlation between NF-kappa B expression and in vitro cytoprotection. High NF-kappa B 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 mu mol/l for AML cells, compared with 12.8 mu mol/l for normal marrow cells. LC-1 was shown to reduce the five individual human NF-kappa B Rel proteins in a dose-dependent manner. The subsequent inhibition of many NF-kappa B-regulated cytokines was also demonstrated. Importantly, sensitivity to LC-1 was correlated with the basal NF-kappa B activity. Consequently, LC-1 treatment provides a proof of principle for the use of NF-kappa B inhibitors in the treatment of AML.