Clioquinol, a therapeutic agent for Alzheimer's disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts
Clioquinol, a therapeutic agent for Alzheimer's disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts
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DOI：
10.1158/0008-5472.can-06-3546
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发表时间：
2007-02-15
期刊：
影响因子：
11.2
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Chen, Di;Cui, Qiuzhi Cindy;Dou, Q. Ping
肿瘤的生长和转移依赖于需要铜辅助因子的血管生成。一直以来，在许多类型的人类癌症中都发现了高水平的铜，包括前列腺癌、乳腺癌、结肠癌和肺癌。最近的研究表明，铜可以作为癌症治疗的一种新的选择性靶点。氯喹诺能够与铜形成稳定的配合物，目前用于临床治疗阿尔茨海默病。最近，有报道称氯喹诺具有抗肿瘤作用。然而，潜在的分子机制尚不清楚。我们在此报道，氯喹诺与铜结合后，可以抑制蛋白酶体凝乳胰蛋白酶样活性，抑制雄激素受体（AR）蛋白表达，诱导人前列腺癌LNCaP和C4-2B细胞凋亡。此外，氯喹诺单独对铜浓度升高的前列腺癌细胞系显示出类似的效果，其浓度与患者相似。在两种前列腺癌细胞系中，添加双氢睾酮不影响氯喹啉介导的蛋白酶体抑制。然而，双氢睾酮仅在雄激素依赖性LNCaP细胞中部分抑制氯喹啉诱导的AR抑制和凋亡。动物研究表明，氯喹诺显著抑制人前列腺肿瘤C4-2B异种移植物的生长（66%），与体内蛋白酶体抑制、AR蛋白抑制、血管生成抑制和细胞凋亡诱导有关。我们的研究提供了强有力的证据，证明氯喹诺能够在体内以铜依赖的方式靶向肿瘤蛋白酶体，从而形成一种活性AR抑制剂和细胞凋亡诱导剂，这是其观察到的抗前列腺肿瘤作用的原因。
Tumor growth and metastasis depend on angiogenesis that requires the cofactor copper. Consistently, high levels of copper have been found in many types of human cancers, including prostate, breast, colon, and lung. Recent studies suggest that copper could be used as a novel selective target for cancer therapies. Clioquinol is capable of forming stable complexes with copper and currently used in clinics for treatment of Alzheimer's disease. Most recently, it has been reported that clioquinol possesses antitumor effects. However, the underlying molecular mechanism is unclear. We report here that after binding to copper, clioquinol can inhibit the proteasomal chymotrypsin-like activity, repress androgen receptor (AR) protein expression, and induce apoptotic cell death in human prostate cancer LNCaP and C4-2B cells. In addition, clioquinol alone exhibits similar effects in prostate cancer cell lines with elevated copper at concentrations similar to those found in patients. Addition of dihydrotestosterone did not affect clioquinol-mediated proteasome inhibition in both prostate cancer cell lines. However, dihydrotestosterone partially inhibited clioquinol-induced AR suppression and apoptosis only in androgen-dependent LNCaP cells. Animal studies show that clioquinol treatment significantly inhibits the growth of human prostate tumor C4-2B xenografts (by 66%), associated with in vivo proteasome inhibition, AR protein repression, angiogenesis suppression, and apoptosis induction. Our study provides strong evidence that clioquinol is able to target tumor proteasome in vivo in a copper-dependent manner, resulting in formation of an active AR inhibitor and apoptosis inducer that is responsible for its observed antiprostate tumor effect.