title: Chemosensitizing AML cells by targeting bone marrow endothelial cells.
abstract: Refractory disease is the greatest challenge in treating patients with acute myeloid leukemia (AML). Blood vessels may serve as sanctuary sites for AML. When AML cells were co-cultured with bone marrow endothelial cells (BMECs), a greater proportion of leukemia cells were in G0/G1. This led us to a strategy of targeting BMECs with tubulin-binding combretastatins, causing BMECs to lose their flat phenotype, degrade their cytoskeleton, cease growth, and impair migration despite unchanged BMEC viability and metabolism. Combretastatins also caused downregulation of BMEC adhesion molecules known to tether AML cells, including vascular cell adhesion molecule (VCAM)-1 and vascular endothelial (VE)-cadherin. When AML-BMEC co-cultures were treated with combretastatins, a significantly greater proportion of AML cells dislodged from BMECs and entered the G2/M cell cycle, suggesting enhanced susceptibility to cell cycle agents. Indeed, the combination of combretastatins and cytotoxic chemotherapy enhanced additive AML cell death. In vivo mice xenograft studies confirmed this finding by revealing complete AML regression after treatment with combretastatins and cytotoxic chemotherapy. Beyond highlighting the pathologic role of BMECs in the leukemia microenvironment as a protective reservoir of disease, these results support a new strategy for using vascular-targeting combretastatins in combination with cytotoxic chemotherapy to treat AML.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL. Electronic address: rbosse@ufl.edu.
authors.forename: Raphael C
authors.initials: RC
authors.lastname: Bosse
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Briana
authors.initials: B
authors.lastname: Wasserstrom
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wise
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Leylah
authors.initials: L
authors.lastname: Drusbosky
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Walter
authors.affiliation: OXiGENE, Inc., South San Francisco, CA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.affiliation: Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Purich
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
mesh_terms: D000208:Acute Disease; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D017382:Reactive Oxygen Species / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D013267:Stilbenes; C414983:combretastatin B-1; D003561:Cytarabine