Doxorubicin-induced activation of NF-κB in melanoma cells is abrogated by inhibition of IKKβ, but not by a novel IKKα inhibitor.

Drug resistance is arguably the most important challenge in cancer therapy. Here, doxorubicin induced profound of NF-κB 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 IKKα inhibitor (BAY32-5915) was identified and characterized, and doxorubicin-induced NF-κB activation was assessed following inhibition of IKKα or IKKβ by small-molecular compounds. While the IKKα inhibitor did not affect doxorubicin-induced NF-κB activation, this process was completely abrogated when the IKKβ inhibitor, KINK-1, was used. Moreover, inhibition of IKKβ, but not IKKα, 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-κB activation, blocking IKKβ, but not IKKα, by small molecules can antagonize this activity and, thus, increase chemosensitivity.