Hartman Institute for Therapeutic Organ Regeneration

Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis.

TitleArsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis.
Publication TypeJournal Article
Year of Publication2000
AuthorsRoboz GJ, Dias S, Lam G, Lane WJ, Soignet SL, Warrell RP, Rafii S
JournalBlood
Volume96
Issue4
Pagination1525-30
Date Published2000 Aug 15
ISSN0006-4971
KeywordsAntineoplastic Agents, Apoptosis, Arsenic Trioxide, Arsenicals, Cells, Cultured, Dose-Response Relationship, Drug, Endothelium, Vascular, Humans, Leukemia, Neovascularization, Pathologic, Oxides, Time Factors
Abstract

Arsenic trioxide (As(2)O(3)) has recently been used successfully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro. However, the mechanism by which As(2)O(3) exerts its antileukemic effect remains uncertain. Emerging data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that activated endothelial cells release cytokines that may stimulate leukemic cell growth. Leukemic cells, in turn, can release endothelial growth factors, such as vascular endothelial growth factor (VEGF). On the basis of these observations, we hypothesized that As(2)O(3) may interrupt a reciprocal loop between leukemic cells and the endothelium by direct action on both cell types. We have shown that treatment of proliferating layers of human umbilical vein endothelial cells (HUVECs) with a variety of concentrations of As(2)O(3) results in a reproducible dose- and time-dependent sequence of events marked by change to an activated morphology, up-regulation of endothelial cell adhesion markers, and apoptosis. Also, treatment with As(2)O(3) caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVECs with As(2)O(3) prevented capillary tubule and branch formation in an in vitro endothelial cell-differentiation assay. In conclusion, we believe that As(2)O(3 )interrupts a reciprocal stimulatory loop between leukemic cells and endothelial cells by causing apoptosis of both cell types and by inhibiting leukemic cell VEGF production. (Blood. 2000;96:1525-1530)

Alternate JournalBlood
PubMed ID10942401
Grant ListR01-HL-58707 / HL / NHLBI NIH HHS / United States
R01-HL-61849 / HL / NHLBI NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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