摘要
数十年来,成年和胚胎干细胞新的治疗应用的发展一直主导着再生医学和组织工程。然而,自2006年以来,诱导多能干细胞(iPSC)已成为该领域的中心问题,因为它们有望克服其他干细胞类型的一些局限性。尽管如此,多年来,甚至在产生iPSC之前,还尝试了其他有前途的成年细胞重编程方法。尤其是在发现iPSC的两年前,合成大型有机化合物库的可能性以及开发高通量筛选以快速测试其生物学活性的可能性,使人们得以鉴定2,6-二取代嘌呤,被称为可逆的,被证明能够将成年细胞重编程为祖细胞样状态。自从发现以来,已经证实了可逆在不同细胞类型上的作用,并且对其作用机理的多项研究表明,它在抑制与细胞周期调控和胞质分裂有关的几种激酶的抑制活性中起着核心作用。这些关键特征及其化学性质表明该分子有可能用作抗癌药。值得注意的是,可逆性药物在体外对几种肿瘤细胞系表现出有效的细胞毒活性,并且在降低体内肿瘤的进展和转移方面具有显著作用。因此,自发现以来已有15年的时间,本综述旨在批判性地总结现有知识,以阐明可逆性作为去分化剂和抗癌药的双重作用。
关键词: 逆转,去分化,重编程,重新定位,抗癌,抗肿瘤药物。
[http://dx.doi.org/10.1084/jem.1.4.656] [PMID: 19866819]
[http://dx.doi.org/10.1002/path.1187] [PMID: 12115858]
[http://dx.doi.org/10.1016/S0092-8674(01)00409-3] [PMID: 11439179]
[http://dx.doi.org/10.1186/s13287-018-0913-2] [PMID: 29895321]
[http://dx.doi.org/10.1098/rstb.2017.0229]
[http://dx.doi.org/10.1038/s41569-018-0013-0] [PMID: 29743563]
[http://dx.doi.org/10.1007/s00018-013-1462-6] [PMID: 24158496]
[http://dx.doi.org/10.1126/science.316.5830.1422b] [PMID: 17556566]
[http://dx.doi.org/10.1146/annurev-cellbio-100913-013132] [PMID: 25150008]
[http://dx.doi.org/10.15436/2471-0598.17.022] [PMID: 29104965]
[http://dx.doi.org/10.1016/S0076-6879(06)20012-0] [PMID: 17161701]
[http://dx.doi.org/10.1126/science.1116447] [PMID: 16123299]
[http://dx.doi.org/10.1038/nature04955] [PMID: 16810240]
[http://dx.doi.org/10.1016/S0960-9822(01)00459-6] [PMID: 11591326]
[http://dx.doi.org/10.1038/385810a0] [PMID: 9039911]
[http://dx.doi.org/10.1016/j.cell.2006.07.024] [PMID: 16904174]
[http://dx.doi.org/10.1038/nbt987] [PMID: 15229546]
[http://dx.doi.org/10.1006/dbio.1995.1085] [PMID: 7729574]
[http://dx.doi.org/10.1080/13813450601094631] [PMID: 17178600]
[http://dx.doi.org/10.1038/nature07042] [PMID: 18480815]
[http://dx.doi.org/10.1038/73753] [PMID: 10700146]
[http://dx.doi.org/10.1016/j.chembiol.2005.07.011] [PMID: 16242654]
[http://dx.doi.org/10.1038/sj.cdd.4401958] [PMID: 16729034]
[http://dx.doi.org/10.1021/ja037390k] [PMID: 14719906]
[http://dx.doi.org/10.1002/anie.200460346] [PMID: 15300685]
[http://dx.doi.org/10.2174/138920111794295828] [PMID: 21044013]
[http://dx.doi.org/10.1038/s41586-018-0087-1] [PMID: 29769670]
[http://dx.doi.org/10.1007/s00395-017-0655-9] [PMID: 29079873]
[http://dx.doi.org/10.1002/sctm.17-0138] [PMID: 29072369]
[http://dx.doi.org/10.5966/sctm.2014-0090] [PMID: 25122691]
[http://dx.doi.org/10.1038/nature09781] [PMID: 21248838]
[http://dx.doi.org/10.1002/embr.201338254] [PMID: 24531722]
[http://dx.doi.org/10.3892/ijo.31.6.1293] [PMID: 17982654]
[http://dx.doi.org/10.1007/s10565-016-9333-1] [PMID: 27156576]
[http://dx.doi.org/10.1038/nrm881] [PMID: 12154368]
[http://dx.doi.org/10.1126/science.1077857] [PMID: 12481136]
[http://dx.doi.org/10.1016/j.tibtech.2009.02.007] [PMID: 19395104]
[http://dx.doi.org/10.1146/annurev.cellbio.24.110707.175336] [PMID: 18598212]
[http://dx.doi.org/10.1021/ja0170302] [PMID: 11853431]
[http://dx.doi.org/10.1124/mi.4.2.5] [PMID: 15087481]
[http://dx.doi.org/10.1093/nar/gnh001] [PMID: 14704358]
[http://dx.doi.org/10.1016/S0014-4827(03)00179-4] [PMID: 12878168]
[http://dx.doi.org/10.1083/jcb.127.6.1755] [PMID: 7798324]
[http://dx.doi.org/10.1073/pnas.0704360104] [PMID: 17566101]
[http://dx.doi.org/10.1038/nrm1743] [PMID: 16227978]
[http://dx.doi.org/10.1006/bbrc.1999.1132] [PMID: 10448085]
[http://dx.doi.org/10.1038/35012097] [PMID: 10821277]
[http://dx.doi.org/10.1002/pmic.200700636] [PMID: 17973295]
[http://dx.doi.org/10.3727/096368915X686823] [PMID: 25647295]
[http://dx.doi.org/10.1038/nrm2763] [PMID: 19738629]
[http://dx.doi.org/10.1002/elps.200800800] [PMID: 19582720]
[http://dx.doi.org/10.1186/1479-7364-4-5-353] [PMID: 20650822]
[http://dx.doi.org/10.1074/jbc.M804055200] [PMID: 19015271]
[http://dx.doi.org/10.1089/ten.tea.2009.0343] [PMID: 19947906]
[http://dx.doi.org/10.1038/ng1725] [PMID: 16380711]
[http://dx.doi.org/10.1016/j.bbrc.2014.02.002] [PMID: 24513286]
[http://dx.doi.org/10.1158/1535-7163.MCT-07-2051] [PMID: 18483302]
[http://dx.doi.org/10.1038/cdd.2008.156] [PMID: 18974773]
[http://dx.doi.org/10.1083/jcb.152.4.669] [PMID: 11266459]
[http://dx.doi.org/10.1089/ten.tea.2010.0692] [PMID: 22519969]
[http://dx.doi.org/10.7150/ijbs.12199] [PMID: 26722217]
[PMID: 22051168]
[http://dx.doi.org/10.1002/jcb.24296] [PMID: 22821411]
[PMID: 22451181]
[http://dx.doi.org/10.1002/cbf.3187] [PMID: 27121349]
[http://dx.doi.org/10.1021/cb2000154] [PMID: 21322636]
[http://dx.doi.org/10.1021/cb200532v] [PMID: 22270490]
[http://dx.doi.org/10.2174/1574892810666150617112230] [PMID: 26081925]
[http://dx.doi.org/10.1002/pros.21247] [PMID: 20809552]
[http://dx.doi.org/10.1001/jama.280.11.951] [PMID: 9749464]
[http://dx.doi.org/10.1038/sj.onc.1208068] [PMID: 15361837]
[http://dx.doi.org/10.2174/1574892810666150317144511] [PMID: 25782916]
[http://dx.doi.org/10.1083/jcb.201001036] [PMID: 20624901]
[http://dx.doi.org/10.18632/oncotarget.16213] [PMID: 28415765]
[http://dx.doi.org/10.1002/prot.25174] [PMID: 27699881]
[http://dx.doi.org/10.1007/s11095-012-0727-3] [PMID: 22477067]
[http://dx.doi.org/10.1007/s10616-012-9520-8] [PMID: 23475158]
[http://dx.doi.org/10.1007/s12282-012-0400-z] [PMID: 22926505]
[http://dx.doi.org/10.1016/j.leukres.2016.06.011] [PMID: 27447890]
[http://dx.doi.org/10.2147/OTT.S158198] [PMID: 29520153]
[http://dx.doi.org/10.1371/journal.pone.0158587] [PMID: 27385117]
[http://dx.doi.org/10.1002/jcb.24197] [PMID: 22615034]
[http://dx.doi.org/10.1097/CAD.0000000000000563] [PMID: 28984683]
[http://dx.doi.org/10.1186/1423-0127-19-9] [PMID: 22283874]
[http://dx.doi.org/10.1016/j.biopha.2012.08.001] [PMID: 23089471]
[http://dx.doi.org/10.1038/sj.onc.1207521] [PMID: 15077152]
[http://dx.doi.org/10.1016/j.semcancer.2013.06.007] [PMID: 23811268]
[http://dx.doi.org/10.3390/cancers10010018] [PMID: 29329237]
[http://dx.doi.org/10.3233/CBM-160238] [PMID: 28269749]
[http://dx.doi.org/10.1038/bjc.2013.675] [PMID: 24169345]
[PMID: 24778030]
[http://dx.doi.org/10.1038/nm.2112] [PMID: 20228816]
[http://dx.doi.org/10.1038/ncomms6662] [PMID: 25489927]
[http://dx.doi.org/10.1186/1476-4598-5-55] [PMID: 17081305]
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3383] [PMID: 15087397]
[http://dx.doi.org/10.1073/pnas.1111840108] [PMID: 22068913]
[PMID: 7199383]
[http://dx.doi.org/10.3892/ijo.17.3.501] [PMID: 10938390]
[http://dx.doi.org/10.1002/ijc.28940] [PMID: 24789362]
[http://dx.doi.org/10.18632/oncotarget.6432] [PMID: 26637805]
[http://dx.doi.org/10.1016/j.devcel.2012.06.013] [PMID: 22898774]
[http://dx.doi.org/10.1126/science.1167000] [PMID: 19150808]
[http://dx.doi.org/10.1101/gad.233700.113] [PMID: 24402315]
[http://dx.doi.org/10.1126/science.aaa4029] [PMID: 26068854]
[http://dx.doi.org/10.4161/cc.20621] [PMID: 22592527]