Lonidamine causes inhibition of angiogenesis-related endothelial cell functions.
The aim of this study was to assess whether lonidamine (LND) interferes with some steps in angiogenesis progression. We report here, for the first time, that LND inhibited angiogenic-related endothelial cell functions in a dose-dependent manner (1-50 microg/ml). In particular, LND decreased proliferation, migration, invasion, and morphogenesis on matrigel of different endothelial cell lines. Zymographic and Western blot analysis assays showed that LND treatment produced a reduction in the secretion of matrix metalloproteinase-2 and metalloproteinase-9 by endothelial cells. Vessel formation in a matrigel plug was also reduced by LND. The viability, migration, invasion, and matrix metalloproteinase production of different tumor cell lines were not affected by low doses of LND (1-10 microg/ml), whereas 50 microg/ml LND, which corresponds to the dose used in clinical management of tumors, triggered apoptosis both in endothelial and tumor cells. Together, these data demonstrate that LND is a compound that interferes with endothelial cell functions, both at low and high doses. Thus, the effect of LND on endothelial cell functions, previously undescribed, may be a significant contributor to the antitumor effect of LND observed for clinical management of solid tumors.
Del Bufalo
Donatella
D
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy. delbufalo@ifo.it
Trisciuoglio
Daniela
D
Scarsella
Marco
M
D'Amati
Giulia
G
Candiloro
Antonio
A
Iervolino
Angela
A
Leonetti
Carlo
C
Zupi
Gabriella
G
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007797:Laminin / Q000008:administration & dosage; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000096:biosynthesis; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011509:Proteoglycans / Q000008:administration & dosage; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007191:Indazoles; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C016371:lonidamine