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

New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasmacells (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 inseveral tumours, including MM. However, there is incomplete understand-ing of how EDN1 axis regulates MM growth and response to therapy.Besides EDNRA, the majority of MM cell lines and primary malignant PCsexpress high levels of EDNRB and release EDN1. Similarly, bone-marrowmicroenvironment cells also secrete EDN1. Investigating the extent of epi-genetic dysregulation of EDNRB gene in MM, we found that hypermethyla-tion of EDNRB promoter and subsequent down-regulation of EDNRB genewas observed in PCs or B lymphocytes from healthy donors compared toEDNRB-expressing malignant PCs. Pharm acological blockade with the dualEDN1 receptor antagonist bosentan decreased cell viability and MAPK acti-vation of U266 and RPMI-8226 cells. Interestingly, the combination ofbosentan and the proteasome inhibitor bortezomib, currently approved forMM treatment, resulted in synergistic cytotoxic effects. Overall, our datahas uncovered EDN1-mediated autocrine and paracrine mechanisms thatregulate malignant PCs growth and drug response, and support EDN1receptors as new therapeutic targets in MM.