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.