Anticancer agent CHS 828 suppresses nuclear factor-κB activity in cancer cells through downregulation of ikk activity
Anticancer agent CHS 828 suppresses nuclear factor-κB activity in cancer cells through downregulation of ikk activity
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DOI：
10.1002/ijc.20255
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发表时间：
2004-08-20
影响因子：
6.4
通讯作者：
Madsen, MW
中科院分区：
文献类型：
--
作者：
Olsen, LS;Hjarnaa, PJV;Madsen, MW
CHS 828是一种吡啶基氰基胍，在体内外的临床前试验中已被证明具有显著的抗肿瘤作用，CHS 828正处于I/II期临床试验。我们研究了CHS 828对核因子-kappaB(NF-kappaB)的影响，因为它在控制细胞分裂和凋亡方面具有众所周知的作用。CHS 828能够抑制脂多糖(LPS)诱导的人THP-I白血病细胞中核转录因子-kappaB的转录活性和核定位。此外，CHS 828还被证明可以抑制脂多糖诱导的THP-I细胞中IkappaBalpha和IkappaBβ的降解，从而使我们确定IkappaB激酶复合体是CHS 828的一个分子靶点。CHS 828抑制IKK活性，其IC50为8 nM。不同CHS 828类似物对IKK活性的抑制作用与体内外对NYH小细胞肺癌细胞增殖的抑制作用密切相关。此外，CHS 828对不同癌细胞株转录活性的抑制在一定程度上与CHS 828缩小相应异种移植瘤的大小有关。核因子-kappaB的激活被证明可以诱导抗凋亡蛋白的表达，并且癌细胞被证明具有高水平的结构性活性的核因子-kappaB。因此，我们推测CHS 828的抗癌活性是由于抑制了IKK活性，从而消除了核因子-kappaB的抗凋亡保护，从而促进了细胞凋亡。(C)2004年Wiley-Liss公司
CHS 828, a pyridyl cyanoguanidine, has been shown to exert a significant antitumor effect in preclinical tests in vitro and in vivo, and CHS 828 is in phase I/II clinical trials. We have investigated the effect of CHS 828 on the nuclear factor-kappaB (NF-kappaB) because of its well-known role in the control of cell division and apoptosis. CHS 828 is able to inhibit the lipopolysaccharicle (LPS)-induced nuclear localization as well as the transcriptional activity of NF-kappaB in human THP-I leukemia cells. Moreover, CHS 828 has also been shown to inhibit the LPS-induced degradation of the IkappaBalpha and IkappaBbeta in THP-I cells, leading us to identify the IkappaB kinase complex as a molecular target of CHS 828. The IKK activity is inhibited by CHS 828 with an IC50 of 8 nM. The inhibition of the IKK activity by different CHS 828 analogues correlates well with the inhibition of NYH small cell lung cancer cell proliferation in vitro and in vivo. Moreover, the inhibition of NF-kappaB transcriptional activity in different cancer cell lines by CHS 828 correlates to some extent with the reduction by CHS 828 of the size of the corresponding xenografts. Activation of NF-kappaB has been shown to induce expression of antiapoptotic proteins, and cancer cells have been shown to have high levels of constitutively active NF-kappaB. Therefore, we hypothesize that the anticancer activity of CHS 828 is due to inhibition of the IKK activity by which the antiapoptotic protection of NF-kappaB is removed, leading to the promotion of apoptosis. (C) 2004 Wiley-Liss, Inc.