期刊文献+
任意字段
题名或关键词
题名
关键词
文摘
作者
第一作者
机构
刊名
分类号
参考文献
作者简介
基金资助
栏目信息

PHA-767491抑制多种肿瘤细胞生长 被引量：5

PHA-767491 Inhibits Growth of Tumor Cells in Culture
下载PDF
导出
摘要 Cdc7激酶抑制剂PHA-767491是最新发现的一类抗肿瘤新药.本实验利用不同浓度的PHA-767491对肿瘤细胞进行抑制研究.实验结果显示,PHA-767491对肿瘤细胞有很强的生长抑制作用,且抑制效果随着药物浓度或时间的增加而增强;通过和化疗药物5-氟尿嘧啶对比发现,PHA-767491只需较低剂量就能发挥出抑制肿瘤的作用,且疗效远高于5-氟尿嘧啶.研究进一步还发现,PHA-767491可通过促使PARP和casepase3蛋白的剪切诱导肿瘤细胞凋亡,同时PHA-767491还可以引起肿瘤细胞自噬.综上研究表明,PHA-767491可以通过诱导细胞凋亡和引起细胞自噬作用对多种肿瘤细胞有较好的治疗效果,而对正常细胞毒性很低.因此该实验研究为今后抗肿瘤新药PHA-767491的进一步应用于癌症的临床治疗提供了重要的实验依据. Cdc7 kinase inhibitor PHA-767491 is a novel antitumor agent. This study aims to examine the antitumor activity of PHA-767491 against tumor cells and search for its molecular mechanism. Here we demonstrated that PHA-767491 played a critical role in the suppression of the proliferation of tumor cells in a concentration-and time-dependent manner. Compared with conventional chemotherapeutic drug 5-fluorouracil （5-FU）,PHA-767491 showed a stronger antitumor effect at lower doses. In addition,we found that PHA-767491 induced remarkable apoptosis,evidenced by the cleavage of PARP and caspase 3,and autophagy also be observed in PHA-767491-treated tumor cells. We reported for the first time that PHA-767491 induced tumor cell death via apoptosis and autophagy,and appeared to be less cytotoxic for normal cell. These results suggest that Cdc7 kinase inhibitor PHA-767491 could be a new strategy for the development of anticancer therapeutics.
作者 李伟 张静 胡徐庞 魏旭斌 刘立 钱程
机构地区 浙江理工大学生命科学学院 浙江大学医学院
出处 《中国生物化学与分子生物学报》 CAS CSCD 北大核心 2010年第5期455-461,共7页 Chinese Journal of Biochemistry and Molecular Biology
基金 国家重点基础研究发展规划(973计划 No.2004CB518804) 国家高科技研究发展计划基金项目(863计划 No.2006AA02Z126)~~
关键词 Cdc7激酶 PHA-767491 肿瘤 凋亡 自噬 Cdc7 PHA-767491 tumor apoptosis autophagy
分类号 Q78 [生物学—分子生物学]
  • 相关文献

参考文献11

  • 1李伟,田雪君,刘立,钱程.huCdc7激酶及其与肿瘤的关系[J].生物化学与生物物理进展,2009,36(7):810-816. 被引量：5
  • 2Masai H, Sato N, Takeda T, et al. CDC7 kinase complex as a molecular switch for DNA replication [J]. Front Biosci, 1999,4 : D834-840.
  • 3Masai H, Arai K. Cdc7 kinase complex: a key regulator in the initiation of DNA replication [J]. 2002,190 (3) :287-296.
  • 4Tenca P, Brotherton D, Montagnoli A, et al. Cdc7 is an active kinase in human cancer cells undergoing replication stress [ J]. J Biol Chem,2007,282( 1 ) :208-215.
  • 5Shreeram S, Sparks A, Lane D P. Cell type-specific responses of human cells to inhibition of replication licensing[ J]. Oncogene, 2002, 21 (43) :6624-6632.
  • 6Montagnoli A, Valsasina B, Croci V, et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity [ J ]. Nat Chem Biol, 2008,4 ( 6 ) :357-365.
  • 7Hess GF, Drong RF, Weiland KL,et al. A human homolog of the yeast CDC7 gene is overexpressed in some tumors and transformed cell lines[ J]. Gene, 1998,211 ( 1 ) : 133-140.
  • 8Montagnoli A, Tenca P, Sola F,et al. Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells[ J]. Cancer Res,2004,64 ( 19 ) :7110-7116.
  • 9Im JS, Lee JK. ATR-dependent activation of p38 MAP kinase is responsible for apoptotie cell death in cells depleted of Cdc7 [ J ]. J Biol Chem,2008,283(37) :25171-25177.
  • 10Vanotti E, Amicl R, Bargiotti A,et al. Cdc7 klnase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships [ J ]. J Med Chem, 2008,51 (3) :487-501.

二级参考文献34

  • 1Montagnoli A,Valsasina B,Croci V,et al.A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.Nat Chem Biol,2008,4(6):357～365
  • 2Jackson A L,Pahl P M,Harrison K,et al.Cell cycle regulation of the yeast Cdc7 protein kinase by association with the Dbf4 protein.Mol Cell Biol,1993,13(5):2899～1908
  • 3Montagnoli A,Bosotti R,Villa F,et al.Drfl,a novel regulatory subunit for human Cdc7 kinase.EMBO J,2002,21(12):3171 3181
  • 4Kumagai H,Sato N,Yamada M,et al.A novel growth-and cell cycle-regulated protein,ASK,activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells.Mol Cell Biol,1999,19(7):5083～5095
  • 5Masai H,Matsui E,You Z,et al.Human Cdc7-related kinase complex.In vitro phospborylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cde7 by Cdks.J Biol Chem,2000,275(37):29042～29052
  • 6Yamada M,Sato N,Taniyama C,et al.A 63 base-pair DNA segment containing a Sp1 site but not a canonical E2F site can confer growth-dependent and E2F-mediated transcriptional stimulation of the human ASK gene encoding the regulatory subunit for human Cdc7-related kinase.J Biol Chem,2002,277(31):27668～27681
  • 7Kim J M,Yamada M,Masai H,et al.Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development.Mutat Res,2003,532(1～2):29～40
  • 8Ogino K,Takeda T,Matsui E,et al.Bipartite binding of a kinase activator activates Cdc7-related kinase essential for S phase.J Biol Chem,2001,276(33):31376～31387
  • 9Masai H,Arai K.Cdc7 kinase complex:a key regulator in the initiation of DNA replication.J Cell Physiol,2002,190(3):287～296
  • 10Sato N,Sato M,Nakayama M,et al.Cell cycle regulation of chromatin binding and nuclear localization of human Cdc7-ASK kinase complex.Genes Cells,2003,8(5):451～463

共引文献4

同被引文献81

  • 1樊卫兵,张其善,许宗泽.多重直扩信号的捕获方法研究与实现[J].通信学报,1996,17(6):56-61. 被引量：2
  • 2Rabinowitz JD, White E. Autophagy and metabolism [ J ]. Science,2010, 330 ( 6009 ) : 1344-1348.
  • 3Funderburk SF, Wang QJ, Yue Z. The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond[J]. Trends Cell Biol, 2010, 20(6) :355-362.
  • 4Delgado M, Singh S, De Haro S, et al. Autophagy and pattern recognition receptors in innate immunity [ J ]. Immunol Rev, 2009, 227( 1 ) : 189-202.
  • 5Lee HK, Lund JM, Ramanathan B, et al. Autophagy-dependent viral recognition by plasmacytoid dendritic cells [ J ]. Science, 2007, 315(5817) :1398-1401.
  • 6Puneet P, McGrath MA, Tay HK, et al. The helminth product ES-62 protects against septic shock via Toll-like receptor 4- dependent autophagosomal degradation of the adaptor MyD88 [J]. Natlmmunol, 2011, 12 (4) :344-351.
  • 7Shrivastava S, Raychoudhuri A, Steele R, et al. Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes [ J ]. Hepatology, 2011,53 ( 2 ) :406-414.
  • 8Saitoh T, Fujita N, Hayashi T, et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response[J].Proc Natl Acad Sci USA, 2009,106 ( 49 ) : 20842- 20846.
  • 9Gutierrez MG, Master SS, Singh SB, et al. Autophagy is a defense mechanism inhibiting BCG and mycobacteriumtuberculosis survival in infected macrophages [ J ]. Cell, 2004, 119 (6) : 753-766.
  • 10Scherz-Shouval R, Shvets E, Fass E, et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4 [ J]. EMBO J, 2007, 26 (7) : 1749-1760.

引证文献5

二级引证文献23

中国生物化学与分子生物学报
2010年 第5期

相关作者

内容加载中请稍等...

相关机构

内容加载中请稍等...

相关主题

内容加载中请稍等...

浏览历史

内容加载中请稍等...
;
使用帮助 返回顶部