HIV protease inhibitors have potent antiangiogenesis, antitumor effects
Kaposi’s sarcoma (KS) affects 20% of patients living with AIDS who are not receiving any form of anti-HIV therapy. It leads to the formation of small blood vessels, which in turn form small tumours that manifest as lesions on the skin, mouth and lymph nodes.
Recent observations have demonstrated that HIV-patients treated with highly active antiretroviral therapy (HAART), a drug regimen that constitutes at least one protease inhibitor (PI) such as indinavir or saquinavir, displayed a reduced incidence and increased regression of KS. Since protease inhibitors have also demonstrated a role in angiogenic and inflammatory processes and tumour growth, Barbara Ensoli and colleagues hypothesized that the lower incidence and regression of KS observed in PI-treated patients was, in part, attributable to the direct anti-KS and anti-angiogenic effects of these agents.
To explore this further, preclinical models to evaluate the efficacy of protease inhibitors as potential anti-angiogenic agents, were employed. Using nude mice (devoid of T cells) and the chorioallantoic membrane (Cam) assay (an established in vivo assay that is used to measure angiogenesis), the researchers set out to investigate the effects of indinavir and saquinavir in KS development.
Nude mice were treated with either indinavir or saquinavir and subsequently inoculated with different strains of KS cells. These cells were found to promote the development of KS-like lesions in 100% of mice that had remained untreated. By contrast, in mice that had received either indinavir or saquinavir, lesion development was significantly reduced with only 43% and 25% of these mice displaying macroscopic lesions, respectively. This provided the first evidence of the involvement of PIs in the inhibition of KS development.
To ascertain whether this effect was direct, PIs were tested in another system in which the inflammatory cytokines, bFGF and VEGF – potent angiogenic agents – were used to induce lesions. Using bFGF alone, 71% of the untreated mice developed lesions whereas those that received indinavir and saquinavir, lesion formation was inhibited to 28% and 25%, respectively. Similarly, using a combination of VEGF and bFGF, PI treatment led to a reduction in lesion formation from 83% in untreated mice to 33% and 17% in indinavir and saquinavir-treated mice, respectively. These results further supported the ability of PIs to mediate direct anti-angiogenic effects.
Current anti-angiogenic and anti-tumour therapies are based on blocking endothelial cell invasion, a process that requires the degradation of the basement membrane by matrix metalloproteinase-2. To elucidate the mechanism underlining PI-mediated KS inhibition, gel-activity assays were performed to determine whether these PIs exerted an effect on MMP-2 activity. Although little effect was observed on MMP-2 synthesis, both indinavir and saquinavir were found to block the conversion of MMP-2 into its active form.
All these results serve to strengthen the role of protease inhibitors as promising anti-angiogenic and anti-tumour agents in the treatment of KS and other HIV-associated tumours.
Source: Nature Medicine 2002; 8:225–232