Sabarubicin-(MEN 10755) and Paclitaxel Show Different Kinetics in Nuclear Factor-KappaB (NF-kB) Activation: Effect of Parthenolide on their Cytotoxicity

Abstract

Background: Several antitumor drugs have been described to induce nuclear factor kappaB (NF-Î B), but results about its role in regulating apoptotic cell death are quite controversial. In this paper, we studied NF-Î B induced by the two anticancer agents Sabarubicin (MEN 10755) and paclitaxel (Taxol) and the effects of its pharmacological inhibition. Materials and Methods: In the human colon cancer cell line HCT-116, we investigated NF-Î B 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-Î B inhibitor parthenolide increased Sabarubicin-but not paclitaxel-induced cell death. EMSA experiments demonstrated that the two antitumor drugs induced NF-Î B complexes with different kinetics but similar subunit composition. Moreover, Sabarubicin elicited NF-Î B activation definitely earlier than DNA fragmentation, whereas with paclitaxel the kinetics of the two phenomena were similar.