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

Jenkins, Christopher, Hewamana, Saman, Gilkes, Amanda F., Neelakantan, Sundar, Crooks, Peter, Mills, Ken, Pepper, Christopher John and Burnett, Alan Kenneth 2008. Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia. British Journal of Haematology 143 (5) , pp. 661-671. 10.1111/j.1365-2141.2008.07392.x

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Abstract

Nuclear factor-jB (NF-jB) 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-jB in human myeloid blasts and a clear correlation between NF-jB expression and in vitro cytoprotection. High NF-jB 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 4Æ5 lmol/l for AML cells, compared with 12Æ8 lmol/l for normal marrow cells. LC-1 was shown to reduce the five individual human NF-jB Rel proteins in a dose-dependent manner. The subsequent inhibition of many NF-jB-regulated cytokines was also demonstrated. Importantly, sensitivity to LC-1 was correlated with the basal NF-jB activity. Consequently, LC-1 treatment provides a proof of principle for the use of NF-jB inhibitors in the treatment of AML.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: acute myeloid leukaemia, nuclear factor-jB, cytokines, therapy
Publisher: Wiley-Blackwell
ISSN: 0007-1048
Last Modified: 25 Jun 2017 03:18
URI: http://orca.cf.ac.uk/id/eprint/26164

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