Cusack J C, Liu R, Houston M, Abendroth K, Elliott P J, Adams J, Baldwin A S
Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Cancer Res. 2001 May 1;61(9):3535-40.
Inducible activation of nuclear factor-kappaB (NF-kappaB) inhibits the apoptotic response to chemotherapy and irradiation. Activation of NF-kappaB via phosphorylation of an inhibitor protein IkappaB leads to degradation of IkappaB through the ubiquitin-proteasome pathway. We hypothesized that inactivation of proteasome function will inhibit inducible NF-kappaB 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 microM) prior to exposure to SN-38, the active metabolite of the topoisomerase I inhibitor, CPT-11. Inducible activation of NF-kappaB 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-kappaB 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 = 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-kappaB 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.
核因子-κB（NF-κB）的可诱导激活会抑制对化疗和放疗的凋亡反应。通过抑制蛋白IkappaB的磷酸化激活NF-κB会导致IkappaB通过泛素-蛋白酶体途径降解。我们推测蛋白酶体功能失活将抑制可诱导的NF-κB激活，从而增加对化疗的凋亡水平并增强抗肿瘤作用。为了评估蛋白酶体抑制对化疗反应的影响，在暴露于拓扑异构酶I抑制剂CPT-11的活性代谢物SN-38之前，用人二肽硼酸类似物PS-341（1 microM）预处理人结肠癌细胞。在体外和体内评估NF-κB的可诱导激活和生长反应。确定对p53、p21、p27和凋亡的影响。用PS-341预处理可抑制SN-38诱导的NF-κB激活，与单独使用PS-341（20-30%）或单独使用SN-38（24-47%；P<0.002）相比，生长抑制水平显著更高（64-75%）。联合治疗导致肿瘤大小与对照组相比减少了94%，与所有治疗组相比，对治疗的杀肿瘤反应显著改善（P = 0.02）。与单独使用单一药物治疗（10%）相比，接受联合治疗的治疗组凋亡水平为80-90%。蛋白酶体抑制可阻断化疗诱导的NF-κB激活，导致化疗敏感性显著增强和凋亡增加。将蛋白酶体抑制与化疗联合使用具有克服化疗耐药性高发生率的巨大潜力。目前正在进行临床研究以评估蛋白酶体抑制作为全身化疗重要辅助手段的作用。
