Human immunodeficiency virus protease inhibitors reduce the growth of human tumors via a proteasome-independent block of angiogenesis and matrix metalloproteinases.
Human immunodeficiency virus protease inhibitors (HIV-PIs), such as indinavir and saquinavir, have been shown to block angiogenesis and tumor cell invasion and to induce tumor cell apoptosis and growth arrest, respectively, both in vitro and in vivo. These findings have suggested that HIV-PIs or their analogues can be used as antitumor drugs. To this regard, indinavir and saquinavir were assessed for their ability to inhibit in vivo the growth of highly prevalent human tumors, such as lung, breast, colon and hepatic adenocarcinomas. We show here that both HIV-PIs significantly inhibited the growth of all adenocarcinomas tested in the mice model. This was not mediated by effects on proteasome-dependent cell growth arrest or on apoptosis but by the block of angiogenesis and matrix metalloproteinase activity. Accordingly, therapeutic steadystate concentrations of indinavir or saquinavir were highly effective in inhibiting invasion of tumor cells in vitro. In contrast, growth arrest was induced only by high concentrations of saquinavir that are not reached or are only transiently present in plasma of treated patients, likely through a proteasome-mediated mechanism. These data suggest that HIV-PIs or their analogues, characterized by a better biodistribution and lower toxicity, may represent a new class of antitumor drugs capable of targeting both matrix metalloproteinases and the proteasome for a most effective antitumor therapy.
Toschi
Elena
E
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Sgadari
Cecilia
C
Malavasi
Laura
L
Bacigalupo
Ilaria
I
Chiozzini
Chiara
C
Carlei
Davide
D
Compagnoni
Daniela
D
Bellino
Stefania
S
Bugarini
Roberto
R
Falchi
Mario
M
Palladino
Clelia
C
Leone
Patrizia
P
Barillari
Giovanni
G
Monini
Paolo
P
Ensoli
Barbara
B
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D019469:Indinavir / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019258:Saquinavir / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D017320:HIV Protease Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019469:Indinavir; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D046988:Proteasome Endopeptidase Complex; D019258:Saquinavir