Trabectedin is active against malignant pleural mesothelioma cell and xenograft models and synergizes with chemotherapy and Bcl-2 inhibition in vitro

Mir A. Hoda, Christine Pirker, Yawen Dong, Karin Schelch, Petra Heffeter, Kushtrim Kryeziu, Sushilla Van Schoonhoven, Thomas Klikovits, Viktoria Laszlo, Anita Rozsas, Judit Ozsvar, Walter Klepetko, B. Döme, Michael Grusch, Balazs Hegedüs, Walter Berger

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9 Citations (Scopus)

Abstract

Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or nonadherent spheroids with IC50 values ≤ 2.6 nmol/L. Nonmalignant mesothelial cells were significantly less responsive. The strong antimesothelioma activity was based on cell-cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by coadministration of cisplatin, a drug routinely used for systemic MPM treatment. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl-2 expression. Accordingly, bcl-2 inhibitors (Obatoclax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bcl-2, bim, bax, Mcl-1, and bcl-xL as a consequence of trabectedin exposure. In addition, trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Together, these data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors in vitro. Thus, it represents a promising new therapeutic option for MPM.

Original languageEnglish
Pages (from-to)2357-2369
Number of pages13
JournalMolecular Cancer Therapeutics
Volume15
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hoda, M. A., Pirker, C., Dong, Y., Schelch, K., Heffeter, P., Kryeziu, K., Van Schoonhoven, S., Klikovits, T., Laszlo, V., Rozsas, A., Ozsvar, J., Klepetko, W., Döme, B., Grusch, M., Hegedüs, B., & Berger, W. (2016). Trabectedin is active against malignant pleural mesothelioma cell and xenograft models and synergizes with chemotherapy and Bcl-2 inhibition in vitro. Molecular Cancer Therapeutics, 15(10), 2357-2369. https://doi.org/10.1158/1535-7163.MCT-15-0846