Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution.
Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution.
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DOI：
10.18632/oncotarget.9245
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发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Cater MA
中科院分区：
文献类型：
--
作者：
Denoyer D;Pearson HB;Clatworthy SA;Smith ZM;Francis PS;Llanos RM;Volitakis I;Phillips WA;Meggyesy PM;Masaldan S;Cater MA
提高细胞内生物可利用铜的铜离子载体在体外和小鼠前列腺腺癌（TRAMP）小鼠中显示出显著的治疗作用。然而，尽管即将进行临床试验，其抗癌活性的药理学基础仍不清楚。本研究表明，前列腺癌细胞内铜水平在体外和TRAMP小鼠疾病进展过程中与铜离子载体活性无关，反映了患者前列腺切除术组织中观察到的正常水平（Gleason评分7和9）。TRAMP腺癌细胞具有明显升高的氧化应激和谷胱甘肽（GSH）介导的抗氧化能力降低，这两者共同赋予了对促氧化离子铜的选择性敏感性。铜离子载体处理[CuII(gtsm)，双硫仑和clioquinol]在TRAMP腺癌细胞中产生毒性水平的活性氧（ROS），但在正常小鼠前列腺上皮细胞（PrECs）中没有。本研究结果为铜离子载体的药理活性提供了依据，并提示其可用于前列腺癌患者的治疗。此外，最近的体外和小鼠异种移植研究表明，前列腺癌细胞对铜的需求增加。我们证明了前列腺腺癌在TRAMP小鼠中的发展需要铜的功能性供应，并且明显受到全身铜分布改变的阻碍。在TRAMP小鼠中，铜转运Atp7b蛋白突变体（tx突变：A4066G/Met1356Val）的存在改变了铜在血清中的整合，显著降低了前列腺癌负担（减少64%）和疾病严重程度（等级），消除了腺癌的发展。讨论了对当前临床试验的影响。
Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed.
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影响因子：
2.8
作者：
Denoyer, Delphine;Clatworthy, Sharnel A. S.;Cater, Michael A.
通讯作者：
Cater, Michael A.
DOI：
10.1016/j.bbamcr.2012.06.019
发表时间：
2012-10
影响因子：
5.1
作者：
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通讯作者：
Aw, Tak Yee
DOI：
10.1073/pnas.1116227108
发表时间：
2012-01-03
影响因子：
11.1
作者：
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通讯作者：
Crouch, Peter J.
影响因子：
11.2
作者：
Chen, Di;Cui, Qiuzhi Cindy;Dou, Q. Ping
通讯作者：
Dou, Q. Ping
影响因子：
6.6
作者：
Allensworth JL;Evans MK;Bertucci F;Aldrich AJ;Festa RA;Finetti P;Ueno NT;Safi R;McDonnell DP;Thiele DJ;Van Laere S;Devi GR
通讯作者：
Devi GR