title: Endothelial cell derived angiocrine support of acute myeloid leukemia targeted by receptor tyrosine kinase inhibition.
abstract: In acute myeloid leukemia (AML), refractory disease is a major challenge and the leukemia microenvironment may harbor refractory disease. Human AML cell lines KG-1 and HL-60 expressed receptors also found on endothelial cells (ECs) such as VEGFRs, PDGFRs, and cKit. When human AML cells were co-cultured with human umbilical vein endothelial cells (HUVECs) and primary bone marrow endothelial cell (BMECs), the AML cells were more resistant to cytarabine chemotherapy, even in transwell co-culture suggesting angiocrine regulation. Primary BMECs secreted significantly increased levels of VEGF-A and PDGF-AB after exposure to cytarabine. Pazopanib, a receptor tyrosine kinase inhibitor (RTKI) of VEGFRs, PDGFRs, and cKit, removed EC protection of AML cells and enhanced AML cell sensitivity to cytarabine. Xenograft modeling showed significant regression of AML cells and abrogation of BM hypervascularity in RTKI treated cohorts. Together, these results show direct cytotoxicity of RTKIs on AML cells and reversal of EC protection. Combining RTKIs with chemotherapy may serve as promising therapeutic strategy for patients with AML.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Leylah
authors.initials: L
authors.lastname: Drusbosky
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Gars
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Angelica
authors.initials: A
authors.lastname: Trujillo
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Christie
authors.initials: C
authors.lastname: McGee
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Meacham
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wise
authors.affiliation: Program in Stem Cell Biology and Regenerative Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Scott
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address: christopher.cogle@medicine.ufl.edu.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007191:Indazoles; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D007191:Indazoles; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C095477:platelet-derived growth factor AB; D003561:Cytarabine; C516667:pazopanib; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor