Nuclear factor-kappaB, induced in human carcinoma cell line A2780 by the new anthracycline men 10755, is devoid of transcriptional activity.
The new disaccharide anthracycline MEN 10755 induces activation of both NF-kappaB and p53 transcription factors in A2780 cells. Nevertheless, pharmacologic inhibition of NF-kappaB activation does not modify the sensitivity of A2780 cells to MEN 10755 treatment. To better characterize the role of NF-kappaB in MEN 10755-induced cytotoxicity, we analyzed the expression of a number of genes that are known to be regulated by NF-kappaB. None of these genes is modified by MEN 10755 treatment. On the contrary, our results suggest that the p53 DNA damage-responsive pathway is fully activated in A2780 cells, several genes controlled by p53 being up- or downregulated according to the described action of p53 on their promoters. Thus, in the A2780 cell line, the role of p53 in transducing the DNA-damage signal appears to be relevant, whereas NF-kappaB, although activated, appears to be nonfunctional. Other human carcinoma cell lines besides A2780 activate NF-kappaB DNA binding in response to MEN 10755 treatment, but again, this binding does not always lead to target gene activation. These results suggest that other factors, tumor type-specific and different from mere activation, could influence NF-kappaB transcriptional activity. Therefore, care should be taken when considering the pharmacologic inhibition of NF-kappaB as a means to improve anticancer therapy efficacy.
Camarda
Grazia
G
Department of Pharmacology, Menarini Ricerche, Pomezia, Rome, Italy.
Binaschi
Monica
M
Maggi
Carlo A
CA
Goso
Cristina
C
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism*; D004187:Disaccharides / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004187:Disaccharides; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C107602:sabarubicin