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HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma

Nature Medicine volume 8, pages 225–232 (2002)Cite this article

Abstract

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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Figure 1: PIs block the formation and promote necrosis of angiogenic KS-like lesions induced by the inoculation of KS cells in nude mice.
Figure 2: PIs block the formation of bFGF-induced angiogenic lesions in nude mice.
Figure 3: PIs block the invasion but not the growth of endothelial and KS cells and inhibit the conversion of latent MMP-2 to its active form.

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Acknowledgements

We thank G. Moracci, R. Marinelli and C. Ciccolella for technical help; and A. Lippa and A. Carinci for editorial assistance. I.B. was a recipient of a fellowship from the Federazione Italiana per la Ricerca sul Cancro (FIRC). This study was supported by grants from the Italian Ministry of Health (IX AIDS project) and the Associazione Italiana per la Ricerca sul Cancro (AIRC) to B.E. and to F.B., and from the Italian Ministry of Education, University and Research (MIUR) to G.B.

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Authors and Affiliations

  1. Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy

    Cecilia Sgadari, Giovanni Barillari, Elena Toschi, Davide Carlei, Ilaria Bacigalupo, Sara Baccarini, Clelia Palladino, Patrizia Leone, Laura Malavasi, Aurelio Cafaro, Paolo Monini & Barbara Ensoli

  2. Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanità, Rome, Italy

    Roberto Bugarini & Giovanni Rezza

  3. Laboratory of Ultra Structures, Istituto Superiore di Sanità, Rome, Italy

    Mario Falchi

  4. Department of Experimental Medicine, University 'Tor Vergata', Rome, Italy

    Giovanni Barillari

  5. Department of Oncological Sciences, Institute for Cancer Research and Treatment, University of Turin, Turin, Italy

    Donatella Valdembri & Federico Bussolino

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Correspondence to Barbara Ensoli.

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Sgadari, C., Barillari, G., Toschi, E. et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 8, 225–232 (2002). https://doi.org/10.1038/nm0302-225

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