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

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.

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

“…Protease inhibitors can affect important cellular processes such as angiogenesis, tumor growth and invasion, inflammation, antigen processing and presentation, cell survival, tissue remodelling and metastasis (Sgadari et al, 2003). Protease inhibitors have direct antiproliferative and antiangiogenic effects in vitro, and inhibit the development of KS-like lesions in animal models by blocking an enzyme required for the production of infectious HHV-8 particles (Pati et al, 2002;Sgadari et al, 2002Sgadari et al, , 2003. In clinical trials, PI-containing regimens led to full remission from KS in approximately 50% of patients, and conferred an added survival benefit (Burdick et al, 1997;Aboulafia, 1998;Krischer et al, 1998;Cattelan et al, 1999;De Milito et al, 1999;Paparizos et al, 2002;Leitch et al, 2003;Sgadari et al, 2003).…”

“…Kaposi's sarcoma lesions are characterised by neoangiogenesis and proliferation of spindle cells of endothelial origin, including cells of lymphatic lineage (Dupin et al, 1999). Although experimental studies have shown that PI may have specific antiangiogenic and antiproliferative properties, their specific impact on the clinical outcome of KS has been discussed (Sgadari et al, 2002(Sgadari et al, , 2003. Complete remission of KS has been reported in patients receiving PI, and also relapses after switching to NNRTI-based regimens (Murdaca et al, 2002;Bani-Sadr et al, 2003).…”

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

“…In western countries, KS incidence has remarkably diminished as the implementation of highly active anti-retroviral therapy. This strategy, that allows immune rescue and Human immunodeficiency virus (HIV) replication control, frequently leads to clinical regression of most KS lesions without the need for specific chemotherapies (Sgadari et al, 2002;Monini et al, 2009). However, although KS tends to decline upon antiretroviral treatment, paradoxical aggravations have been described during the early treatment period, where recovery is generally slow (Mitsuyasu, 2000;Maurer et al, 2007).…”

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

“…It was, however, found that these compounds also affect cellular processes such as angiogenesis, inflammation, the antigen processing and presentation process, cell survival and cell-cycle progression and tissue remodelling [3,[22][23][24]. Data suggest that targets of these drugs may include the PI3K/Akt signalling pathway, nuclear factor jB, signal transducers and activators of transcription 3 (STAT3), matrix metalloproteinase, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) [25][26][27][28][29][30].…”