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

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.

In reply to Schäfer et al: new evidence on the role of endothelin‐1 axis as a potential therapeutic target in multiple myeloma

“…Vaiou et al () previously demonstrated a protective role for EDNRB in bortezomib‐treated NCI‐H929 and RPMI‐8226 cells, showing that the MAPK pathway was the predominant signalling pathway involved in EDN1/EDNRB‐induced bortezomib resistance. In our paper (Russignan et al , ), a synergistic effect of bosentan and bortezomib in both U266 and RPMI‐8226 cells was demonstrated. Interestingly, new data (see Fig.…”

“…We thank Dr. Schäfer and colleagues for their interest in our study (Russignan et al , ) and to better reflect our current understanding of the role of the endothelin‐1 (EDN1) axis as a therapeutic target in multiple myeloma (MM). We reply to the criticisms they raised about our work by providing further findings that envision the possibility of interfering with EDN1 receptor activity in exploring a novel therapeutic strategy for MM patients.…”

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells

“…Recently, it has been observed an abnormal expression of endothelin receptor type B (EDNRB) in hepatocellular carcinoma and confirmed its potential clinical significance (Zhang et al 2019). Thus, endothelin-1 receptor blockade is new possible therapeutic approach in multiple myeloma, because the majority of multiple myeloma cell lines and primary malignant plasma cells express high levels of EDNRA and EDNRB and release EDN1 (Russignan et al 2017).…”

Bosentan enhances in vitro bortezomib's anti‐proliferative potency against multiple myeloma by mechanisms going beyond endothelin receptor blockade

“…Most recently, experimental data reported by Russignan et al () underlined previous data. Their data again suggests an important role of the endothelin axis in multiple myeloma, which can be functionally blocked by bosentan, an EDNRA and EDNRB antagonist (Russignan et al , ).…”