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 journalArticle

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

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trabectedin
Juvenile Myelomonocytic Leukemia
Leukemia, Myelomonocytic, Chronic
Neoplasms
Granulocyte-Macrophage Progenitor Cells
Cell Line
rho GTP-Binding Proteins
Cell Lineage
Growth
Hematopoietic Stem Cells
DNA Repair
Bone Marrow Cells
Monocytes

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

Cite this

Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms. / Romano, Michela; Della Porta, Matteo Giovanni; Gallì, Anna; Panini, Nicolò; Licandro, Simonetta Andrea; Bello, Ezia; Craparotta, Ilaria; Rosti, Vittorio; Bonetti, Elisa; Tancredi, Richard; Rossi, Marianna; Mannarino, Laura; Marchini, Sergio; Porcu, Luca; Galmarini, Carlos M; Zambelli, Alberto; Zecca, Marco; Locatelli, Franco; Cazzola, Mario; Biondi, Andrea; Rambaldi, Alessandro; Allavena, Paola; Erba, Eugenio; D'Incalci, Maurizio.

In: British Journal of Cancer, Vol. 116, No. 3, 01.2017, p. 335-343.

Research output: Contribution to journalArticle

Romano, M, Della Porta, MG, Gallì, A, Panini, N, Licandro, SA, Bello, E, Craparotta, I, Rosti, V, Bonetti, E, Tancredi, R, Rossi, M, Mannarino, L, Marchini, S, Porcu, L, Galmarini, CM, Zambelli, A, Zecca, M, Locatelli, F, Cazzola, M, Biondi, A, Rambaldi, A, Allavena, P, Erba, E & D'Incalci, M 2017, 'Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms', British Journal of Cancer, vol. 116, no. 3, pp. 335-343. https://doi.org/10.1038/bjc.2016.424
Romano, Michela ; Della Porta, Matteo Giovanni ; Gallì, Anna ; Panini, Nicolò ; Licandro, Simonetta Andrea ; Bello, Ezia ; Craparotta, Ilaria ; Rosti, Vittorio ; Bonetti, Elisa ; Tancredi, Richard ; Rossi, Marianna ; Mannarino, Laura ; Marchini, Sergio ; Porcu, Luca ; Galmarini, Carlos M ; Zambelli, Alberto ; Zecca, Marco ; Locatelli, Franco ; Cazzola, Mario ; Biondi, Andrea ; Rambaldi, Alessandro ; Allavena, Paola ; Erba, Eugenio ; D'Incalci, Maurizio. / Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms. In: British Journal of Cancer. 2017 ; Vol. 116, No. 3. pp. 335-343.
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T1 - Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

AU - Romano, Michela

AU - Della Porta, Matteo Giovanni

AU - Gallì, Anna

AU - Panini, Nicolò

AU - Licandro, Simonetta Andrea

AU - Bello, Ezia

AU - Craparotta, Ilaria

AU - Rosti, Vittorio

AU - Bonetti, Elisa

AU - Tancredi, Richard

AU - Rossi, Marianna

AU - Mannarino, Laura

AU - Marchini, Sergio

AU - Porcu, Luca

AU - Galmarini, Carlos M

AU - Zambelli, Alberto

AU - Zecca, Marco

AU - Locatelli, Franco

AU - Cazzola, Mario

AU - Biondi, Andrea

AU - Rambaldi, Alessandro

AU - Allavena, Paola

AU - Erba, Eugenio

AU - D'Incalci, Maurizio

PY - 2017/1

Y1 - 2017/1

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents, Alkylating

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Dioxoles

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Leukemia, Myelomonocytic, Chronic

KW - Leukemia, Myelomonocytic, Juvenile

KW - Mice

KW - Mice, Nude

KW - Myelodysplastic Syndromes

KW - Tetrahydroisoquinolines

KW - Tumor Stem Cell Assay

KW - Journal Article

U2 - 10.1038/bjc.2016.424

DO - 10.1038/bjc.2016.424

M3 - Article

C2 - 28072764

VL - 116

SP - 335

EP - 343

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 3

ER -