title: Trabectedin and its C subunit modified analogue PM01183 attenuate nucleotide excision repair and show activity toward platinum-resistant cells.
abstract: PM01183 is a novel marine-derived covalent DNA binder in clinical development. PM01183 is structurally similar to trabectedin (yondelis, ecteinascidin-743) except for the C subunit, and this modification is accompanied by different pharmacokinetics in cancer patients. We here characterize the interaction of PM01183 with the nucleotide excision repair (NER) pathway in comparison with trabectedin. Our results show for the first time that although neither PM01183 nor trabectedin is repaired by NER, both compounds are able to interfere with the NER machinery thereby attenuating the repair of specific NER substrates. We further show that the NER activity is increased in 3 of 4 cellular models with acquired resistance to cisplatin or oxaliplatin, confirming the involvement of NER in the resistance to platinum derivatives. Importantly, both PM01183 and trabectedin show unchanged or even enhanced activity toward all 4 cisplatin- and oxaliplatin-resistant cell lines. We finally show that combinations of PM01183 and cisplatin were mostly synergistic toward both parental and cisplatin-resistant ovarian carcinoma cells as indicated by Chou and Talalay analysis. These data show that the C subunit of trabectedin can be subjected to at least some structural modifications without loss of activity or NER interaction. While PM01183 and trabectedin appear functionally similar in cellular models, it is likely that the differences in pharmacokinetics may allow different dosing and scheduling of PM01183 in the clinic that could lead to novel and/or increased antitumor activity. Taken together, our results provide a mechanistic basis to support clinical trials of PM01183 alone or in combination with cisplatin.
authors.affiliation: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale U938, Paris, France.
authors.forename: Daniele G
authors.initials: DG
authors.lastname: Soares
authors.forename: Miriana S
authors.initials: MS
authors.lastname: Machado
authors.forename: Céline J
authors.initials: CJ
authors.lastname: Rocca
authors.forename: Virginie
authors.initials: V
authors.lastname: Poindessous
authors.forename: Djamila
authors.initials: D
authors.lastname: Ouaret
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.forename: João A P
authors.initials: JA
authors.lastname: Henriques
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Escargueil
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects*; D004149:Dioxoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D045325:HCT116 Cells; D019073:HT29 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000077606:Trabectedin; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002243:Carbolines; D002843:Chromatin; D004149:Dioxoles; D006576:Heterocyclic Compounds, 4 or More Rings; D009944:Organoplatinum Compounds; C568606:PM 01183; D044005:Tetrahydroisoquinolines; D000077150:Oxaliplatin; D000077606:Trabectedin; D002945:Cisplatin