Advances in Brief Enhanced Chemosensitivity to CPT-11 with Proteasome Inhibitor PS-341 : Implications for Systemic Nuclear Factor-k B Inhibition 1

Inducible activation of nuclear factor-kB (NF-kB) inhibits the apoptotic response to chemotherapy and irradiation. Activation of NF-kB via phosphorylation of an inhibitor protein IkB leads to degradation of IkB through the ubiquitin-proteasome pathway. We hypothesized that inactivation of proteasome function will inhibit inducible NF-kB activation, thereby increasing levels of apoptosis in response to chemotherapy and enhancing antitumor effects. To assess the effects of proteasome inhibition on chemotherapy response, human colorectal cancer cells were pretreated with the dipeptide boronic acid analogue PS-341 (1 mM) prior to exposure to SN-38, the active metabolite of the topoisomerase I inhibitor, CPT-11. Inducible activation of NF-kB and growth response were evaluated in vitro and in vivo. Effects on p53, p21, p27 and apoptosis were determined. Pretreatment with PS-341 inhibited activation of NF-kB induced by SN-38 and resulted in a significantly higher level of growth inhibition (64–75%) compared with treatment with PS-341 alone (20–30%) or SN-38 alone (24–47%; P < 0.002). Combination therapy resulted in a 94% decrease in tumor size compared with the control group and significantly improved tumoricidal response to treatment compared with all treatment groups (P 5 0.02). The level of apoptosis was 80–90% in the treatment group that received combination treatment compared with treatment with single agent alone (10%). Proteasome inhibition blocks chemotherapy-induced NF-kB activation, leading to a dramatic augmentation of chemosensitivity and enhanced apoptosis. Combining proteasome inhibition with chemotherapy has significant potential to overcome the high incidence of chemotherapy resistance. Clinical studies are currently in development to evaluate the role of proteasome inhibition as an important adjuvant to systemic chemotherapy.