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

Br J Haematol. 2008 Dec;143(5):661-71. doi: 10.1111/j.1365-2141.2008.07392.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis
  • Cytotoxicity Tests, Immunologic
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • NF-kappa B / analysis
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics
  • Oligonucleotide Array Sequence Analysis
  • Sesquiterpenes / therapeutic use*
  • Tumor Cells, Cultured
  • Young Adult


  • Antineoplastic Agents
  • LC-1 compound
  • NF-kappa B
  • Sesquiterpenes