DNA and non-DNA targets in the mechanism of action of the antitumor drug trabectedin

被引:57
|
作者
David-Cordonnier, MH
Gajate, C
Olmea, O
Laine, W
de la Igiesia-Vicente, J
Perez, C
Cuevas, C
Otero, G
Manzanares, I
Bailly, C
Mollinedo, F
机构
[1] Univ Salamanca, Ctr Invest Canc, Inst Biol Mol & Celular Canc, CSIC, E-37007 Salamanca, Spain
[2] INSERM, U 524, F-59045 Lille, France
[3] IRCL, Lab Pharmacol Antitumorale, F-59045 Lille, France
[4] IRCL, Ctr Oscar Lambret, F-59045 Lille, France
[5] Hosp Univ Salamanca, Unidad Invest, E-37007 Salamanca, Spain
[6] PharmaMar, E-28770 Madrid, Spain
来源
CHEMISTRY & BIOLOGY | 2005年 / 12卷 / 11期
关键词
D O I
10.1016/j.chembiol.2005.08.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have analyzed the DNA binding properties of the antitumor agent trabectedin (ET-743, Yondelis) and different analogs, namely, ET-745, lacking the C21-hydroxyl group, and ET-637, ET-594, ET-637-OBu, with modifications at the trabectedin C domain, versus their effects on cell cycle, apoptosis, and gene expression. ET-745 failed to bind DNA, highlighting the importance of the C21-hydroxyl group for DNA binding. Analogs ranked trabectedin >> ET-637 ET-594 > ET-637-013u >> ET-745 for their DNA binding capacity; ET-637 and ET-594 display very different biological activities. Drugs were clustered in three major groups showing high (trabectedin, ET-637), intermediate (ET-637-OBu), and low (ET-594, ET-745) cytotoxic activity and similar transcriptional profiling responses. C21-hydroxyl-deficient analogs of the above-mentioned compounds showed a dramatic decrease in biological activity. Our data suggest that trabectedin interacts with an additional non-DNA target to raise an effective antitumor response, and that this interaction is favored through trabectedin-DNA complexes.
引用
收藏
页码:1201 / 1210
页数:10
相关论文
共 50 条
  • [41] Exploring programmable self-assembly in non-DNA based molecular computing
    Terrazas, German
    Zenil, Hector
    Krasnogor, Natalio
    NATURAL COMPUTING, 2013, 12 (04) : 499 - 515
  • [42] Exploring programmable self-assembly in non-DNA based molecular computing
    Germán Terrazas
    Hector Zenil
    Natalio Krasnogor
    Natural Computing, 2013, 12 : 499 - 515
  • [43] DNA sequence recognition by the antitumor drug ditercalinium
    Crow, SDG
    Bailly, C
    Garbay-Jaureguiberry, C
    Roques, B
    Shaw, BR
    Waring, MJ
    BIOCHEMISTRY, 2002, 41 (27) : 8672 - 8682
  • [44] Inhibition of the shade avoidance response by formation of non-DNA binding bHLH heterodimers
    Hornitschek, Patricia
    Lorrain, Severine
    Zoete, Vincent
    Michielin, Olivier
    Fankhauser, Christian
    EMBO JOURNAL, 2009, 28 (24): : 3893 - 3902
  • [45] Zinc Finger of Replication Protein A, a Non-DNA Binding Element, Regulates Its DNA Binding Activity through Redox
    Park, Jang-Su
    Wang, Mu
    Park, Su-Jung
    Lee, Suk-Hee
    Journal of Biological Chemistry, 274 (41): : 29075 - 29080
  • [46] Antimalarials: Molecular Drug Targets and Mechanism of Action
    Achieng, Angela O.
    Rawat, Manmeet
    Ogutu, Bernhards
    Guyah, Bernard
    Ong'echa, John Michael
    Perkins, Douglas J.
    Kempaiah, Prakasha
    CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2017, 17 (19) : 2114 - 2128
  • [47] Genotoxicity Biomarker Kinetics Provide a Means to Distinguish DNA-reactive versus Non-DNA reactive clastogens
    Bemis, J. C.
    Bernacki, D.
    Bryce, S.
    Dertinger, S.
    ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, 2017, 58 : S68 - S68
  • [48] Action models for the antitumor drug camptothecin: Formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I
    Streltsov, SA
    JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2002, 20 (03): : 447 - 454
  • [49] DNA TOPOISOMERASES AS POTENTIAL TARGETS OF ANTIVIRAL ACTION
    KREUZER, KN
    PHARMACOLOGY & THERAPEUTICS, 1989, 43 (03) : 377 - 395
  • [50] Advanced applications of DNA nanostructures dominated by DNA origami in antitumor drug delivery
    Zhang, Yiming
    Tian, Xinchen
    Wang, Zijian
    Wang, Haochen
    Liu, Fen
    Long, Qipeng
    Jiang, Shulong
    FRONTIERS IN MOLECULAR BIOSCIENCES, 2023, 10