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Mol Cancer Res. 2019 Mar;17(3):773-782. doi: 10.1158/1541-7786.MCR-18-0575. Epub 2018 Dec 14.

The Antitumor Drugs Trabectedin and Lurbinectedin Induce Transcription-Dependent Replication Stress and Genome Instability.

Author information

1
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad Pablo de Olavide-Universidad de Sevilla, Seville, Spain.
2
PharmaMar, Colmenar Viejo, Spain.
3
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad Pablo de Olavide-Universidad de Sevilla, Seville, Spain. aguilo@us.es.

Abstract

: R-loops are a major source of replication stress, DNA damage, and genome instability, which are major hallmarks of cancer cells. Accordingly, growing evidence suggests that R-loops may also be related to cancer. Here we show that R-loops play an important role in the cellular response to trabectedin (ET743), an anticancer drug from marine origin and its derivative lurbinectedin (PM01183). Trabectedin and lurbinectedin induced RNA-DNA hybrid-dependent DNA damage in HeLa cells, causing replication impairment and genome instability. We also show that high levels of R-loops increase cell sensitivity to trabectedin. In addition, trabectedin led to transcription-dependent FANCD2 foci accumulation, which was suppressed by RNase H1 overexpression. In yeast, trabectedin and lurbinectedin increased the presence of Rad52 foci, a marker of DNA damage, in an R-loop-dependent manner. In addition to providing new insights into the mechanisms of action of these drugs, our study reveals that R-loops could be targeted by anticancer agents. Given the increasing evidence that R-loops occur all over the genome, the ability of lurbinectedin and trabectedin to act on them may contribute to enhance their efficacy, opening the possibility that R-loops might be a feature shared by specific cancers. IMPLICATIONS: The data presented in this study provide the new concept that R-loops are important cellular factors that contribute to trabectedin and lurbinectedin anticancer activity.

PMID:
30552231
PMCID:
PMC6398590
[Available on 2019-09-01]
DOI:
10.1158/1541-7786.MCR-18-0575

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