Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

Michela Romano, Matteo Giovanni Della Porta, Anna Gallì, Nicolò Panini, Simonetta Andrea Licandro, Ezia Bello, Ilaria Craparotta, Vittorio Rosti, Elisa Bonetti, Richard Tancredi, Marianna Rossi, Laura Mannarino, Sergio Marchini, Luca Porcu, Carlos M Galmarini, Alberto Zambelli, Marco Zecca, Franco Locatelli, Mario Cazzola, Andrea BiondiAlessandro Rambaldi, Paola Allavena, Eugenio Erba, Maurizio D'Incalci

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN.

METHODS: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines.

RESULTS: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models.

CONCLUSIONS: Trabectedin could be good candidate for clinical studies in JMML/CMML patients.

Original languageEnglish
Pages (from-to)335-343
Number of pages9
JournalBritish Journal of Cancer
Volume116
Issue number3
DOIs
Publication statusPublished - Jan 2017

Keywords

  • Animals
  • Antineoplastic Agents, Alkylating
  • Cell Line, Tumor
  • Cell Proliferation
  • Dioxoles
  • Female
  • Gene Expression Profiling
  • Humans
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, Myelomonocytic, Juvenile
  • Mice
  • Mice, Nude
  • Myelodysplastic Syndromes
  • Tetrahydroisoquinolines
  • Tumor Stem Cell Assay
  • Journal Article

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