title: Unique features of trabectedin mechanism of action.
abstract: Trabectedin (Yondelis®, ET-743) is a marine-derived natural product that was initially isolated from the marine ascidian Ecteinascidia turbinata and is currently prepared synthetically. Trabectedin is used as a single agent for the treatment of patients with soft tissue sarcoma after failure of doxorubicin or ifosfamide or who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin presents a complex mechanism of action affecting key cell biology processes in tumor cells as well as in the tumor microenvironment. The inhibition of trans-activated transcription and the interaction with DNA repair proteins appear as a hallmark of the antiproliferative activity of trabectedin. Inhibition of active transcription is achieved by an initial direct mechanism that involves interaction with RNA polymerase II, thereby inducing its ubiquitination and degradation by the proteasome. This subsequently modulates the production of cytokines and chemokines by tumor and tumor-associated macrophages. Another interesting effect on activated transcription is mediated by the displacement of oncogenic transcription factors from their target promoters, thereby affecting oncogenic signaling addiction. In addition, it is well established that DNA repair systems including transcription-coupled nucleotide excision repair and homologous recombination play a role in the antitumor activity of trabectedin. Ongoing studies are currently addressing how to exploit these unique mechanistic features of trabectedin to combine this agent either with immunological or microenvironmental modulators or with classical chemotherapeutic agents in a more rational manner.
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Sorbonne Universités et Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Hôpital Sant-Antoine, 184 Rue du Faubourg Saint Antoine, 75571, Paris Cédex 12, France.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
authors.affiliation: Cell Biology Department, PharmaMar, Poligono Industrial La Mina, Avda. de los Reyes, 1, 28770, Colmenar Viejo, Madrid, Spain. cgalmarini@pharmamar.com.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.affiliation: Department of Oncology, IRCCS - Istiuto di Ricerche Farmacologiche "Mario Negri", Via La Masa, 19, 20156, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004260:DNA Repair; D004149:Dioxoles / Q000494:pharmacology*; D059765:Homologous Recombination; D006801:Humans; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D059016:Tumor Microenvironment
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
keywords: DNA repair; Pharmacology; Trabectedin; Transcription