Russo S M, Tepper J E, Baldwin A S, Liu R, Adams J, Elliott P, Cusack J C
Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Int J Radiat Oncol Biol Phys. 2001 May 1;50(1):183-93. doi: 10.1016/s0360-3016(01)01446-8.
NF-kappaB is activated by tumor necrosis factor, certain chemotherapeutic agents, and ionizing radiation, leading to inhibition of apoptosis. NF-kappaB activation is regulated by phosphorylation of IkappaB inhibitor molecules that are subsequently targeted for degradation by the ubiquitin-proteasome pathway. PS-341 is a specific and selective inhibitor of the proteasome that inhibits NF-kappaB activation and enhances cytotoxic effects of chemotherapy in vitro and in vivo. The objective of this study was to determine if proteasome inhibition leads to enhanced radiation sensitivity.
Inhibition of NF-kappaB activation in colorectal cancer cells was performed by treatment of LOVO cells with PS-341 or infection with an adenovirus encoding IkappaB super-repressor, a selective NF-kappaB inhibitor. Cells were irradiated at 0, 2, 4, 6, 8, and 10 Gy with or without inhibition of NF-kappaB. NF-kappaB activation was determined by electrophoretic mobility gel shift assay, and apoptosis was evaluated using the TUNEL assay. Growth and clonogenic survival data were obtained to assess effects of treatment on radiosensitization. In vitro results were tested in vivo using a LOVO xenograft model.
NF-kappaB activation was induced by radiation and inhibited by pretreatment with either PS-341 or IkappaBalpha super-repressor in all cell lines. Inhibition of radiation-induced NF-kappaB activation resulted in increased apoptosis and decreased cell growth and clonogenic survival. A 7-41% increase in radiosensitivity was observed for cells treated with PS-341 or IkappaBalpha. An 84% reduction in initial tumor volume was obtained in LOVO xenografts receiving radiation and PS-341.
Inhibition of NF-kappaB activation increases radiation-induced apoptosis and enhances radiosensitivity in colorectal cancer cells in vitro and in vivo. Results are encouraging for the use of PS-341 as a radiosensitizing agent in the treatment of colorectal cancer.
核因子κB（NF-κB）可被肿瘤坏死因子、某些化疗药物及电离辐射激活，进而抑制细胞凋亡。NF-κB的激活受IκB抑制分子磷酸化的调控，随后这些抑制分子通过泛素-蛋白酶体途径被靶向降解。PS-341是一种蛋白酶体特异性选择性抑制剂，可抑制NF-κB的激活，并在体外和体内增强化疗的细胞毒性作用。本研究的目的是确定蛋白酶体抑制是否会导致放射敏感性增强。
通过用PS-341处理LOVO细胞或感染编码IκB超级阻遏物（一种选择性NF-κB抑制剂）的腺病毒，对结肠癌细胞中的NF-κB激活进行抑制。在有或没有NF-κB抑制的情况下，分别以0、2、4、6、8和10 Gy的剂量对细胞进行照射。通过电泳迁移率凝胶迁移试验测定NF-κB的激活情况，并使用TUNEL试验评估细胞凋亡。获取生长和克隆形成存活数据以评估治疗对放射增敏的影响。体外实验结果在LOVO异种移植模型中进行体内验证。
在所有细胞系中，辐射均可诱导NF-κB激活，而用PS-341或IκBα超级阻遏物预处理可抑制该激活。抑制辐射诱导的NF-κB激活会导致细胞凋亡增加，细胞生长和克隆形成存活减少。用PS-341或IκBα处理的细胞放射敏感性提高了7%-41%。接受辐射和PS-341治疗的LOVO异种移植瘤初始肿瘤体积减少了84%。
抑制NF-κB激活可增加辐射诱导的细胞凋亡，并在体外和体内增强结肠癌细胞的放射敏感性。这些结果对于将PS-341用作治疗结肠癌的放射增敏剂来说是令人鼓舞的。
