DNA and Non-DNA Targets in the Mechanism of Action of the Antitumor Drug Trabectedin

Abstract

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.

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

“…1C), whereas the disfavored sequence studied, CGA (34, 35), was not stabilized at all (data not shown). These results are consistent with previous findings using plasmid DNA molecules (35,36) and argues strongly in favor of the view that the hampering of DNA strand separation brought about by the covalent adduct may result in a strong blockade of transcription and replication forks in living cells. This behavior is reminiscent of that elicited by other antineoplastic drugs that give rise to true ICLs such as MMC (37).…”

“…These duplexes encompass the two-hydrogenbond-compliant purine-G-C and pyrimidine-G-G combinations shown in Fig. 1B as well as the more recently characterized AGA triplet for which only one hydrogen bond is possible (34,35). The consistently high increment in melting temperature of dsDNA (average DT m z 20jC) was at least 2-fold greater than that brought about by a tight-binding bisintercalating agent such as echinomycin or thiocoraline (23) and was essentially identical after 15 min or 24 h of incubation in the whole range of drug/DNA ratios studied (1:10 to 1:1).…”

Trabectedin – the DNA minor groove binder

“…1). Эта группа играет главную роль в механизме связывания трабектедина с гуанином, так как лишенное его про-изводное (ЕТ-745) не образует аддуктов с ДНК и обла-дает в 100 раз меньшей цитотоксичностью [3].…”

“…О роли оригинальной структуры домена С для свойств молекулы трабектедина свидетельствуют результаты ряда работ с его химической модифи-кацией, которая приводила к снижению цитоток-сичности производных и утрате способности из-бирательно подавлять систему эксцизионной репарации [3,7]. При этом в одной из работ опи-сано производное, лишенное домена С, которое, по данным авторов, сохранило цитотоксичность трабектедина [8].…”

Ovarian Cancer: BRCA Genetics Reveals Targets for New Therapies

“…Trabectedin has a unique mechanism of action based on interaction with the minor groove of the DNA double helix generating adducts that bend DNA and induce DSBs, it affects gene transcription and DNA repair pathways, resulting in G2-M cell cycle arrest and ultimately apoptosis [69]. Trabectedin cytotoxicity is determined by the functional nucleotide excision repair (NER) and a deficient homologous recombination repair (HRR) machinery.…”