Doxorubicin-induced activation of NF-kappa B in melanoma cells is abrogated by inhibition of IKK beta, but not by a novel IKK alpha inhibitor

Drug resistance is arguably the most important challenge in cancer therapy. Here, doxorubicin induced profound of NF-kappa B activation in melanoma cells with a maximum (3.5-fold) at concentrations relevant in vivo. This was followed by transcriptional induction of several gene products involved in tumor progression. A novel IKKa inhibitor (BAY32-5915) was identified and characterized, and doxorubicin-induced NF-kappa B activation was assessed following inhibition of IKKa or IKK beta by small-molecular compounds. While the IKKa inhibitor did not affect doxorubicin-induced NF-kappa B activation, this process was completely abrogated when the IKK beta inhibitor, KINK-1, was used. Moreover, inhibition of IKK beta, but not IKKa, led to significantly increased apoptosis in response to doxorubicin. Our results indicate that the net outcome of chemotherapy is difficult to predict and may even involve mechanisms conferring chemoresistance. In case of doxorubicin-induced NF-kappa B activation, blocking IKK beta, but not IKK alpha, by small molecules can antagonize this activity and, thus, increase chemosensitivity.