HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma.
Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These PIs also block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol). These effects are mediated by the inhibition of endothelial- and KS-cell invasion and of matrix metalloproteinase-2 proteolytic activation by PIs at concentrations present in plasma of treated individuals. As PIs also inhibit the in vivo growth and invasion of an angiogenic tumor-cell line, these data indicate that PIs are potent anti-angiogenic and anti-tumor molecules that might be used in treating non-HIV KS and in other HIV-associated tumors.
Sgadari
Cecilia
C
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Barillari
Giovanni
G
Toschi
Elena
E
Carlei
Davide
D
Bacigalupo
Ilaria
I
Baccarini
Sara
S
Palladino
Clelia
C
Leone
Patrizia
P
Bugarini
Roberto
R
Malavasi
Laura
L
Cafaro
Aurelio
A
Falchi
Mario
M
Valdembri
Donatella
D
Rezza
Giovanni
G
Bussolino
Federico
F
Monini
Paolo
P
Ensoli
Barbara
B
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005321:Extraembryonic Membranes / Q000503:physiopathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000627:therapeutic use*; D008222:Lymphokines / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D017239:Paclitaxel / Q000494:pharmacology; D019258:Saquinavir / Q000008:administration & dosage / Q000627:therapeutic use*; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D016228:Endothelial Growth Factors; D017320:HIV Protease Inhibitors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D019469:Indinavir; D020778:Matrix Metalloproteinase 2; D019258:Saquinavir; D017239:Paclitaxel