DNA and non-DNA targets in the mechanism of action of the antitumor drug trabectedin.
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 approximately ET-594 > ET-637-OBu >> 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.
David-Cordonnier
Marie-Hélène
MH
INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Lille 59045, France.
Gajate
Consuelo
C
Olmea
Osvaldo
O
Laine
William
W
de la Iglesia-Vicente
Janis
J
Perez
Carlos
C
Cuevas
Carmen
C
Otero
Gabriel
G
Manzanares
Ignacio
I
Bailly
Christian
C
Mollinedo
Faustino
F
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004149:Dioxoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D013379:Substrate Specificity; D013696:Temperature; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D000970:Antineoplastic Agents; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077606:Trabectedin