Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia
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Rossana Maffei1,5,*, Stefania Fiorcari1,*, Tiziana Vaisitti2, Silvia Martinelli1, Stefania Benatti1, Giulia Debbia1, Davide Rossi3,4, Patrizia Zucchini1, Leonardo Potenza1, Mario Luppi1, Gianluca Gaidano4, Silvia Deaglio2 and Roberto Marasca1
1Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
2Department of Medical Sciences, University of Turin and Human Genetics Foundation, Turin, Italy
3Division of Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland
4Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
5Department of Oncology, Hematology and Respiratory Track Diseases, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy
*These authors have contributed equally to this work
Roberto Marasca, email: [email protected]
Keywords: chronic lymphocytic leukemia, endothelin 1, macitentan, ibrutinib, microenvironment
Received: October 15, 2016 Accepted: July 25, 2017 Published: September 27, 2017
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.
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