Alkylphospholipids inhibit capillary-like endothelial tube formation in vitro: antiangiogenic properties of a new class of antitumor agents.
Synthetic alkylphospholipids (APLs), such as edelfosine, miltefosine and perifosine, constitute a new class of antineoplastic compounds with various clinical applications. Here we have evaluated the antiangiogenic properties of APLs. The sensitivity of three types of vascular endothelial cells (ECs) (bovine aortic ECs, human umbilical vein ECs and human microvascular ECs) to APL-induced apoptosis was dependent on the proliferative status of these cells and correlated with the cellular drug incorporation. Although confluent, nondividing ECs failed to undergo apoptosis, proliferating ECs showed a 3-4-fold higher uptake and significant levels of apoptosis after APL treatment. These findings raised the question of whether APLs interfere with new blood vessel formation. To test the antiangiogenic properties in vitro, we studied the effect of APLs using two different experimental models. The first one tested the ability of human microvascular ECs to invade a three-dimensional human fibrin matrix and form capillary-like tubular networks. In the second model, bovine aortic ECs were grown in a collagen gel sandwich to allow tube formation. We found that all three APLs interfered with endothelial tube formation in a dose-dependent manner, with a more than 50% reduction at 25 micromol/l. Interference with the angiogenic process represents a novel mode of action of APLs and might significantly contribute to the antitumor effect of these compounds.
Division of Cellular Biochemistry, Department of Pathology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan, CX Amsterdam, The Netherlands.
Shuraila F
SF
Zerp
Stefan R
SR
Vink
Gerald A
GA
Ruiter
Pieter
P
Koolwijk
Erna
E
Peters
Arnold H
AH
van der Luit
Daphne
D
de Jong
Marianne
M
Budde
Harry
H
Bartelink
Wim J
WJ
van Blitterswijk
Marcel
M
Verheij
D000478:Alkylation; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002417:Cattle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors; D010742:Phospholipid Ethers; D010743:Phospholipids; D010767:Phosphorylcholine; C026659:edelfosine; C105905:perifosine