In vitro and in vivo anti-angiogenic effects of hydroxyurea

Author(s)

Mascia Lopes, Flavia Cristine ^[1] ; Ferreira, Regiane ^[1] ; Albuquerque, Dulcineia Martins ^[1] ; Antoniellis Silveira, Angelica A. ^[1] ; Costa, Raquel ^[2] ; Soares, Raquel ^[2] ; Costa, Fernando Ferreira ^[1] ; Conran, Nicola ^[1]

Affiliation

^[1] Univ Campinas UNICAMP, Sch Med Sci, Hematol & Hemotherapy Ctr, INCT Sangue, Campinas, SP - Brazil

^[2] Univ Porto, Fac Med, Dept Biochem FCT U38, P-4100 Oporto - Portugal

• Document type: Journal article
• Source: MICROVASCULAR RESEARCH; v. 94, p. 106-113, JUL 2014.
• Web of Science Citations: 14

Abstract

Hydroxyurea (HU), or hydroxycarbamide, is used for the treatment of some myeloproliferative and neoplastic diseases, and is currently the only drug approved by the FDA for use in sickle cell disease (SCD). Despite the relative success of HU therapy for SCD, a genetic disorder of the hemoglobin beta chain that results in red-cell sickling, hemolysis, vascular inflammation and recurrent vasoocclusion, the exact mechanisms by which HU actuates remain unclear. We hypothesized that HU may modulate endothelial angiogenic processes, with important consequences for vascular inflammation. The effects of HU (50-200 mu M; 17-24 h) on endothelial cell functions associated with key steps of angiogenesis were evaluated using human umbilical vein endothelial cell (HUVEC) cultures. Expression profiles of the HIFIA gene and the miRNAs 221 and 222, involved in endothelial function, were also determined in HUVECs following HU administration and the direct in vivo antiangiogenic effects of HU were assessed using a mouse Matrigel-plug neovascularization assay. Following incubation with HU, HUVECs exhibited high cell viability, but displayed a significant 75% inhibition in the rate of capillary-like-structure formation, and significant decreases in proliferative and invasive capacities. Furthermore, HU significantly decreased HIF1A expression, and induced the expression of miRNA 221, white downregulating miRNA 222. In vivo, HU reduced vascular endothelial growth factor (VEGF)-induced vascular development in Matrigel implants over 7 days. Findings indicate that HU is able to inhibit vessel assembly, a crucial angiogenic process, both in vitro and in vivo, and suggest that some of HU's therapeutic effects may occur through novel vascular mechanisms. (C) 2014 Elsevier Inc All rights reserved. (AU)

• FAPESP's process: 09/16334-0 - Aspects of angiogenesis in sickle cell anemia
• Grantee: Flávia Cristine Mascia Lopes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 08/57441-0 - Clinical, cellular and molecular alterations in hemoglobinopathies and other hereditary hemolytic anemias
• Grantee: Fernando Ferreira Costa
• Support Opportunities: Research Projects - Thematic Grants