Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma

Anna Russignan, Cecilia Spina, Nicola Tamassia, Adriana Cassaro, Antonella Rigo, Anna Bagnato, Laura Rosanò, Angela Bonalumi, Michele Gottardi, Lucia Zanatta, Alice Giacomazzi, Maria Teresa Scupoli, Martina Tinelli, Ugo Salvadori, Federico Mosna, Alberto Zamò, Marco A Cassatella, Fabrizio Vinante, Cristina Tecchio

Research output: Contribution to journalArticle

Abstract

New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasma cells (PCs) represent attractive new therapeutic targets. The endothelin-1 (EDN1) axis, consisting of EDN1 acting through EDN-receptor A (EDNRA) and B (EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1. Similarly, bone-marrow microenvironment cells also secrete EDN1. Investigating the extent of epigenetic dysregulation of EDNRB gene in MM, we found that hypermethylation of EDNRB promoter and subsequent down-regulation of EDNRB gene was observed in PCs or B lymphocytes from healthy donors compared to EDNRB-expressing malignant PCs. Pharmacological blockade with the dual EDN1 receptor antagonist bosentan decreased cell viability and MAPK activation of U266 and RPMI-8226 cells. Interestingly, the combination of bosentan and the proteasome inhibitor bortezomib, currently approved for MM treatment, resulted in synergistic cytotoxic effects. Overall, our data has uncovered EDN1-mediated autocrine and paracrine mechanisms that regulate malignant PCs growth and drug response, and support EDN1 receptors as new therapeutic targets in MM.

Original languageEnglish
Pages (from-to)781-793
Number of pages13
JournalBritish Journal of Haematology
Volume178
Issue number5
DOIs
Publication statusPublished - Sep 2017

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Autocrine Communication
  • Bortezomib
  • Cell Proliferation
  • Cell Survival
  • DNA Methylation
  • DNA, Neoplasm
  • Drug Synergism
  • Endothelin A Receptor Antagonists
  • Endothelin-1
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Multiple Myeloma
  • Plasma Cells
  • Promoter Regions, Genetic
  • Receptor, Endothelin A
  • Sulfonamides
  • Tumor Cells, Cultured
  • Journal Article
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Russignan, A., Spina, C., Tamassia, N., Cassaro, A., Rigo, A., Bagnato, A., Rosanò, L., Bonalumi, A., Gottardi, M., Zanatta, L., Giacomazzi, A., Scupoli, M. T., Tinelli, M., Salvadori, U., Mosna, F., Zamò, A., Cassatella, M. A., Vinante, F., & Tecchio, C. (2017). Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma. British Journal of Haematology, 178(5), 781-793. https://doi.org/10.1111/bjh.14771