P-365 - Beneficial effects of inhibiting iNOS activity versus iNOS transcription in anti-tumor photodynamic therapy

Abstract

We have shown that various cancer cells can exploit endogenous nitric oxide (NO) to resist elimination by photodynamic therapy (PDT) or cisplatin treatment. Inducible NO synthase (iNOS) was rapidly and persistently upregulated after treatment and the resulting NO signaled not only for greater resistance, but greater growth, migration, and invasion aggressiveness of surviving cells. NO-mediated hyper-aggressiveness has been also observed in non-targeted bystander cells. In the present study involving human glioblastoma U87 cells, we compared the pro-PDT effectiveness of inhibiting iNOS activity, using 1400 W, with inhibiting NF-κB-mediated iNOS transcription, using a BET bromodomain inhibitor (JQ1). iNOS was upregulated 2–3-fold in PDT-treated U87 cells and Bay11–7082 inhibition of NF-κB-activating kinase IKK prevented this response. JQ1 strongly suppressed basal as well as post-PDT iNOS induction. JQ1 synergized with PDT in enhancing either apoptotic cell killing or suppressing hyper-invasiveness of PDT-surviving cells. This is the first evidence for JQ1's superior effectiveness in suppressing iNOS antagonism to an anticancer therapy. Since several BET bromodomain inhibitors are now in clinical trials for various cancers, the translational potential of our findings are clear.