Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia

Abstract

The crosstalk between chronic lymphocytic leukemia (CLL) cells and tumor microenvironment is essential for leukemic clone maintenance, supporting CLL cells survival, proliferation and protection from drug-induced apoptosis. Over the past years, the role of several soluble factors involved in these processes has been studied. CLL cells express higher levels of endothelin 1 (ET-1) and ETA receptor as compared to normal B cells. Upon ET-1 stimulation, CLL cells improve their survival and proliferation and reduce their sensitivity to the phosphoinositide-3-kinase δ inhibitor idelalisib and to fludarabine. Here, we demonstrate that CLL cells express not only ETA receptor but also ETB receptor. ET-1 acts as a homing factor supporting CLL cells migration and adhesion to microenvironmental cells. In addition, ET-1 stimulates a pro-angiogenic profile of CLL cells increasing VEGF expression through hypoxia-inducible factor-1 (HIF-1α) accumulation in CLL cells. Macitentan, a specific dual inhibitor of ETA and ETB receptors, targets CLL cells affecting leukemic cells migration and adhesion and overcoming the pro-survival and proliferation signals mediated by microenvironment. Furthermore, macitentan cooperates with ibrutinib inhibiting the BCR pathway and with ABT-199 disrupting BCL2 pathway. Our data describe the biological effects of a new drug, macitentan, able to counteract essential processes in CLL pathobiology as survival, migration, trafficking and drug resistance. These findings envision the possibility to interfere with ET receptors activity using macitentan as a possible novel therapeutic strategy for CLL patients.

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

“…Importantly, Ambrisentan has already been approved by the FDA and the European Medicines Agency (EMA) for the treatment of PAH 19 , 40 – 42 and connective tissue diseases such as Systemic Sclerosis based on extensive safety, toxicity and efficacy testing 43 . Our findings are in agreement with recent reports showing that the dual-specific ETAR and ETBR antagonist, Macitentan, has the ability to counteract chronic lymphocytic leukemia cells by inhibiting in vitro migration and proliferation 44 , as well as tumor growth and metastasis in resistant ovarian cancer xenografts in mice 45 . Likewise, a recent report from Eun-Ju Im and colleagues found serendipitously that sulfisoxazole, which inhibits exosome secretion, limits the growth and metastasis of MDA-MB-231 and 4T1 cells by targeting ETAR 46 .…”

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

“…Aberrant activation of the EDN1 axis is now recognized as a common mechanism underlying the progression of several solid and blood malignancies (Rosanò et al , ; Rosanò & Bagnato, ; Maffei et al , ). Our study established the presence of the EDN1 axis in human MM.…”

Antiapoptotic Proteins mcl-1 and bcl-2 as well as Growth Factors FGF and VEGF Influence Survival of Peripheral Blood and Bone Marrow Chronic Lymphocytic Leukemia Cells

“…When binded to these receptors VEGF increase apoptotic resistance of cells interact with STAT1 and STAT3 which ends up in upregulation of XIAP and mcl-1 expression (8,21,22). Also VEGFR expression in CLL cells are stimulated by endothelin -1 receptor signaling through hypoxia inducible factor 1, suggesting the impact of endotel cells in CLL survival (23,24). Our results show greater concentration of VEGF in peripheral blood then in bone marrow, as well as a strong connection between mcl-1 expression and concentration of VEGF in peripheral blood, which also suggest that VEGF is secreted in peripheral blood and not overflow from bone marrow.…”