Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia.
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.
Jenkins
Christopher
C
Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK. jenkins800@hotmail.com
Hewamana
Saman
S
Gilkes
Amanda
A
Neelakantan
Sundar
S
Crooks
Peter
P
Mills
Ken
K
Pepper
Chris
C
Burnett
Alan
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D003601:Cytotoxicity Tests, Immunologic; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D055815:Young Adult
D000970:Antineoplastic Agents; C524858:LC-1 compound; D016328:NF-kappa B; D012717:Sesquiterpenes