Sabarubicin- (MEN 10755) and paclitaxel show different kinetics in nuclear factor-kappaB (NF-kB) activation: effect of parthenolide on their cytotoxicity.
BACKGROUND
Several antitumor drugs have been described to induce nuclear factor kappaB (NF-kappaB), but results about its role in regulating apoptotic cell death are quite controversial. In this paper, we studied NF-kappaB induced by the two anticancer agents Sabarubicin (MEN 10755) and paclitaxel (Taxol) and the effects of its pharmacological inhibition.


METHODS
In the human colon cancer cell line HCT-116, we investigated NF-kappaB activation induced by the two anticancer agents using electrophoretic mobility shift assay (EMSA), while drug-induced cytotoxicity was measured by trypan blue staining. Apoptosis was analyzed using a cell death detection enzyme-linked immunosorbent assay (ELISA) kit, flow cytometry and caspase-3 activation assay.


RESULTS
The combination with the NF-kappaB inhibitorparthenolide increased Sabarubicin- but not paclitaxel-induced cell death. EMSA experiments demonstrated that the two antitumor drugs induced NF-kappaB complexes with different kinetics but similar subunit composition. Moreover, Sabarubicin elicited NF-kappaB activation definitely earlier than DNA fragmentation, whereas with paclitaxel the kinetics of the two phenomena were similar.
Bellarosa
Daniela
D
Department of Pharmacology, Menarini Ricerche S.p.A., Pomezia, Italy. pharmacology@menarini-ricerche.it
Binaschi
Monica
M
Maggi
Carlo Alberto
CA
Goso
Cristina
C
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D004187:Disaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*
D004187:Disaccharides; D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D004317:Doxorubicin; D017239:Paclitaxel; C107602:sabarubicin