HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma
Cecilia Sgadari1, Giovanni Barillari1, 4, Elena Toschi1, Davide Carlei1, Ilaria Bacigalupo1, Sara Baccarini1, Clelia Palladino1, Patrizia Leone1, Roberto Bugarini2, Laura Malavasi1, Aurelio Cafaro1, Mario Falchi3, Donatella Valdembri5, Giovanni Rezza2, Federico Bussolino5, Paolo Monini1
& Barbara Ensoli1
1
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy
2
Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanità, Rome, Italy
3
Laboratory of Ultra Structures, Istituto Superiore di Sanità, Rome, Italy
4
Department of Experimental Medicine, University 'Tor Vergata', Rome, Italy
5
Institute for Cancer Research and Treatment, Department of Oncological Sciences, University of Turin, Turin, Italy
Correspondence should be addressed to Barbara Ensoli ensoli@iss.it
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.
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