Zalypsis (PM00104) is a potent inducer of gamma-H2AX foci and reveals the importance of the C ring of trabectedin for transcription-coupled repair inhibition.
Zalypsis (PM00104) is a novel tetrahydroisoquinoline alkaloid related to trabectedin [ecteinascidin 743 (Et743)]. Et743 and PM00104 have similar A and B rings but differ in their C rings. The present study shows that Et743 and PM00104 differ in at least two ways: in their DNA binding properties and nucleotide excision repair (NER) dependency for cellular targeting. DNase I footprinting shows that the two drugs bind DNA differentially. We also found that, in contrast to Et743, the antiproliferative activity of PM00104 does not depend on transcription-coupled NER. Accordingly, PM00104 induces gamma-H2AX foci with the same efficiency in NER-deficient or NER-proficient cells. Moreover, the formation of gamma-H2AX foci is replication dependent for PM00104, whereas it is both transcription and replication dependent in the case of Et743. These findings show the importance of the C ring structure of tetrahydroisoquinoline ecteinascidin derivatives for NER targeting. Finally, PM00104 exerts antiproliferative activity at nanomolar concentrations and induces gamma-H2AX response in two Ewing's sarcoma cell lines, suggesting that gamma-H2AX could serve as a pharmacodynamic biomarker for the clinical development of PM00104.
Guirouilh-Barbat
Josée
J
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
Antony
Smitha
S
Pommier
Yves
Y
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D018983:DNA Footprinting; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004149:Dioxoles / Q000737:chemistry* / Q000494:pharmacology; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D000077606:Trabectedin; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; C468783:H2AX protein, human; D006657:Histones; C500383:PM 00104; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin