Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma

Anna Russignan, Giada Dal Collo, Anna Bagnato, Nicola Tamassia, Mattia Bugatti, Mirella Belleri, Luisa Lorenzi, Enrica Borsi, Riccardo Bazzoni, Michele Gottardi, Carolina Terragna, William Vermi, Arianna Giacomini, Marco Presta, Marco Antonio Cassatella, Mauro Krampera, Cristina Tecchio

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Abstract

The endothelin-1 (ET-1) receptors were recently found to mediate pro-survival functions in multiple myeloma (MM) cells in response to autocrine ET-1. This study investigated the effectiveness of macitentan, a dual ET-1 receptor antagonist, in MM treatment, and the mechanisms underlying its activities. Macitentan affected significantly MM cell (RPMI-8226, U266, KMS-12-PE) survival and pro-angiogenic cytokine release by down-modulating ET-1-activated MAPK/ERK and HIF-1α pathways, respectively. HIF-1α silencing abrogated the ET-1 mediated induction of genes encoding for pro-angiogenic cytokines such as VEGF-A, IL-8, Adrenomedullin, and ET-1 itself. Upon exposure to macitentan, MM cells cultured in the presence of the hypoxia-mimetic agent CoCl2, exogenous ET-1, or CoCl2 plus ET-1, down-regulated HIF-1α and the transcription and release of downstream pro-angiogenic cytokines. Consistently, macitentan limited significantly the basal pro-angiogenic activity of RPMI-8226 cells in chorioallantoic membrane assay. In xenograft mouse models, established by injecting NOG mice either via intra-caudal vein with U266 or subcutaneously with RPMI-8226 cells, macitentan reduced effectively the number of MM cells infiltrating bone marrow, and the size and microvascular density of subcutaneous MM tumors. ET-1 receptors targeting by macitentan represents an effective anti-proliferative and anti-angiogenic therapeutic approach in preclinical settings of MM.

Original languageEnglish
Pages (from-to)600025
JournalFrontiers in Oncology
Volume10
DOIs
Publication statusPublished - 2020
Externally publishedYes

Bibliographical note

FUNDING
This work was supported by: The Alessandro Moretti
Foundation, Verona, Italy, and the Lions Club Dante Alighieri,
Verona, Italy.

Copyright © 2021 Russignan, Dal Collo, Bagnato, Tamassia, Bugatti, Belleri, Lorenzi, Borsi, Bazzoni, Gottardi, Terragna, Vermi, Giacomini, Presta, Cassatella, Krampera and Tecchio.

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