Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia
نویسندگان
چکیده
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.
منابع مشابه
Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist.
Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N'-propylaminosulfonamide], is a new dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity f...
متن کاملMacitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice.
PURPOSE The objective of the study was to determine whether astrocytes and brain endothelial cells protect glioma cells from temozolomide through an endothelin-dependent signaling mechanism and to examine the therapeutic efficacy of the dual endothelin receptor antagonist, macitentan, in orthotopic models of human glioblastoma. EXPERIMENTAL DESIGN We evaluated several endothelin receptor anta...
متن کاملChronic blockade of endothelin A and B receptors using macitentan in experimental renovascular disease.
BACKGROUND Emerging research has identified the endothelin (ET)-1 pathway as a potential target for novel renoprotective therapies. We recently showed that selective ET-A receptor antagonism in chronic renovascular disease (RVD) improves renal function and reduces renal injury. Although ET-A and -B have opposing roles, in some clinical situations they may induce similar effects. Thus, we hypoth...
متن کاملAn Unusual Case Report: Occurrence of Renal Cell Carcinoma, Basal Cell Carcinoma and Chronic Lymphocytic Leukemia in a Case of Papillary Thyroid Carcinoma Treated with Radioactive Iodine
The standard therapy for thyroid cancer is total or near total thyroidectomy, followed by the administration of radioactive iodine for remnant ablation or residual disease. Patients with radioiodine therapy are predisposed to second malignant neoplasms in organs such as central nervous system (CNS), breast, prostate, kidney, bone marrow, salivary gland, and digestive tract. Exposure to carcinog...
متن کاملTHE ROLE OF CD49d IN CHRONIC LYMPHOCYTIC LEUKAEMIA: MICROENVIRONMENTAL INTERACTIONS AND CLINICAL RELEVANCE
Chronic lymphocytic leukaemia (CLL) is a clinically heterogeneous disease characterised by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. Stimulation through the B cell receptor (BCR) plays a prominent role in the selection and expansion of the malignant clone in CL...
متن کامل