Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: Implications for systemic nuclear factor-kappa B inhibition

Inducible activation of nuclear factor-kappaB (NF-kappaB) inhibits the apop totic response to chemotherapy and irradiation. Activation of NF-kappaB via phosphorylation of an inhibitor protein I kappaB leads to degradation of I kappaB through the ubiquitin-proteasome pathway. We hypothesized that inac tivation of proteasome function will inhibit inducible NF-kappaB activation , thereby increasing levels of apoptosis in response to chemotherapy and en hancing antitumor effects, To assess the effects of proteasome inhibition o n chemotherapy response, human colorectal cancer cells were pretreated with the dipeptide boronic acid analogue PS-341 (1 muM) prior to exposure to SN -38, the active metabolite of the topoisomerase I inhibitor, CPT-11, Induci ble activation of NF-kappaB and growth response were evaluated in vitro and in vivo. Effects on p53, p21, p27 and apoptosis were determined. Pretreatm ent with PS-341 inhibited activation of NF-kappaB induced by SN-38 and resu lted 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 < 0.00 2). Combination therapy resulted in a 94% decrease in tumor size compared w ith the control group and significantly improved tumoricidal response to tr eatment compared with all treatment groups (P = 0.02). The level of apoptos is was 80-90% in the treatment group that received combination treatment co mpared with treatment with single agent alone (10%), Proteasome inhibition blocks chemotherapy-induced NF-<kappa>B activation, leading to a dramatic a ugmentation of chemosensitivity and enhanced apoptosis, Combining proteasom e inhibition with chemotherapy has significant potential to overcome the hi gh incidence of chemotherapy resistance. Clinical studies are currently in development to evaluate the role of proteasome Inhibition as an important a djuvant to systemic chemotherapy.