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 d 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 ETAand ETBreceptors, 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.

Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia / Maffei, Rossana; Fiorcari, Stefania; Vaisitti, Tiziana; Martinelli, Silvia; Benatti, Stefania; Debbia, Giulia; Rossi, Davide; Zucchini, Patrizia; Potenza, Leonardo; Luppi, Mario; Gaidano, Gianluca; Deaglio, Silvia; Marasca, Roberto. - In: ONCOTARGET. - ISSN 1949-2553. - 8:52(2017), pp. 90013-90027. [10.18632/oncotarget.21341]

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

Maffei, Rossana;Fiorcari, Stefania;Martinelli, Silvia;Benatti, Stefania;Debbia, Giulia;Zucchini, Patrizia;Potenza, Leonardo;Luppi, Mario;Marasca, Roberto
2017

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 d 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 ETAand ETBreceptors, 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.
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Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia / Maffei, Rossana; Fiorcari, Stefania; Vaisitti, Tiziana; Martinelli, Silvia; Benatti, Stefania; Debbia, Giulia; Rossi, Davide; Zucchini, Patrizia; Potenza, Leonardo; Luppi, Mario; Gaidano, Gianluca; Deaglio, Silvia; Marasca, Roberto. - In: ONCOTARGET. - ISSN 1949-2553. - 8:52(2017), pp. 90013-90027. [10.18632/oncotarget.21341]
Maffei, Rossana; Fiorcari, Stefania; Vaisitti, Tiziana; Martinelli, Silvia; Benatti, Stefania; Debbia, Giulia; Rossi, Davide; Zucchini, Patrizia; Potenza, Leonardo; Luppi, Mario; Gaidano, Gianluca; Deaglio, Silvia; Marasca, Roberto
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1159325
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