Modulation of Wnt/β-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer.
Modulation of Wnt/β-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer.
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DOI：
10.1038/onc.2011.228
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发表时间：
2012-01-12
期刊：
影响因子：
8
通讯作者：
Virshup, D. M.
中科院分区：
文献类型：
--
作者：
Coombs, G. S.;Schmitt, A. A.;Canning, C. A.;Alok, A.;Low, I. C. C.;Banerjee, N.;Kaur, S.;Utomo, V.;Jones, C. M.;Pervaiz, S.;Toone, E. J.;Virshup, D. M.
使用Wnt/β-连环蛋白抑制剂的筛选，鉴定了具有体内抗癌性质的8-羟基喹诺酮衍生物家族。使用连接图数据库对先导化合物N-（（8-羟基-7-喹啉基）（4-甲基苯基）甲基）苯甲酰胺（HQBA）的微阵列数据的分析表明，它是模拟缺氧反应的铁螯合剂。HQBA螯合Fe 2+的解离常数为10−19，与Fe 3+和其他过渡金属的结合要弱得多。HQBA抑制培养物中多种细胞系的增殖，并阻断两种不同的乳腺癌基因工程小鼠模型MMTV-Wnt 1和MMTV-PyMT小鼠中已建立的自发性癌症的进展，而没有明显的毒性。HQBA可抑制调节细胞类型特异性β-连环蛋白驱动的转录的铁依赖性因子。它独立于其对β-连环蛋白信号传导的影响而抑制癌细胞增殖，因为它在MMTV-PyMT肿瘤和不同的β-连环蛋白非依赖性细胞系中同样有效。HQBA是一种很有前途的特异性细胞内Fe 2+螯合剂，具有抗自发性小鼠乳腺癌的活性。
Using a screen for Wnt/β-catenin inhibitors, a family of 8-hydroxyquinolone derivatives with in vivo anti-cancer properties was identified. Analysis of microarray data for the lead compound N-((8-hydroxy-7-quinolinyl) (4-methylphenyl)methyl)benzamide (HQBA) using the Connectivity Map database suggested that it is an iron chelator that mimics the hypoxic response. HQBA chelates Fe2+ with a dissociation constant of ∼10−19 , with much weaker binding to Fe3+ and other transition metals. HQBA inhibited proliferation of multiple cell lines in culture, and blocked the progression of established spontaneous cancers in two distinct genetically engineered mouse models of mammary cancer, MMTV-Wnt1 and MMTV-PyMT mice, without overt toxicity. HQBA may inhibit an iron-dependent factor that regulates cell-type-specific β-catenin-driven transcription. It inhibits cancer cell proliferation independently of its effect on β-catenin signaling, as it works equally well in MMTV-PyMT tumors and diverse β-catenin-independent cell lines. HQBA is a promising specific intracellular Fe2+ chelator with activity against spontaneous mouse mammary cancers.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
2.9
作者：
Sigurskjold, BW
通讯作者：
Sigurskjold, BW
影响因子：
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作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
5.1
作者：
McCulloch, Malcolm W. B.;Bugni, Tim S.;Concepcion, Gisela P.;Coombs, Gary S.;Harper, Mary Kay;Kaur, Simran;Mangalindan, Gina C.;Mutizwa, Misha M.;Veltri, Charles A.;Virshup, David M.;Ireland, Chris M.
通讯作者：
Ireland, Chris M.
影响因子：
3.5
作者：
McCulloch, Malcolm W. B.;Coombs, Gary S.;Banerjee, Nikhil;Bugni, Tim S.;Cannon, Kendell M.;Harper, Mary Kay;Veltri, Charles A.;Virshup, David M.;Ireland, Chris M.
通讯作者：
Ireland, Chris M.