Effetti anti-angiogenici e anti-tumorali degli inibitori delle proteasi dell'HIV in un modello murino di cancro alla cervice uterina

Cervical cancer is one of the most common malignancy worldwide. The primary cause of its development is the infection by human papillomavirus (HPV), mainly types 16 and 18, that are acquired above all through sexual activity. Recently, in developed countries, there are different screening systems and two new vaccines have been commercialized. However, we will have to wait for a long time before being able to observe a significant impact of these preventive strategies on incidence and recurrence of cervical tumor. Moreover, in less developed countries, treatment programs and health care are inaccessible to the affected women. The aim of this work has been to find new therapies able to prevent or inhibit cervical cancer progression. Previous studies have shown that HIV-protease inhibitors (HIV-PIs), a class of antiretroviral drugs included in highly antiretroviral therapy (HAART) administrated to HIV-positive patients, were able to reduce incidence and/or regression of HIV-associated tumors. It has been demonstrated that this regression was not only the result of HIV suppression and restoration of immune response, but was determined by a direct anti-angiogenic and anti-tumor action. We have performed our studies using the transgenic mouse model HPV16/E2, that recapitulates the human steps of neoplastic progression developing cervical intraepithelial lesions (CIN) that spontaneously progress to invasive cervical carcinomas. We have performed a prevention-intervention trial administrating HIV-PIs Indinavir (Ind) and Saquinavir (Saq), as single drugs or in combination with Ritonavir (Rtv), to HPV16/E2 mice from 3.5 to 5 months of age, aimed to prevent or regress tumor progression and angiogenesis. Optimal doses were defined by employing increasing doses and combinations of the drugs. Our data demonstrated a strong anti-angiogenic and anti-tumor effect of HIV-PIs. Of note, HIV-PIs indirectly inhibited tumor growth by inducing vessel apoptosis and consequently tumor cell death. Remarkably, HIV-PIs treatments completely inhibited matrix metalloproteases (MMPs) activity in tumors suggesting that these proteases are one of the main targets of the drugs in cervical cancer. MMPs are involved in the release and mobilization of VEGF from the matrix. Our data revealed that PIs, inhibiting MMPs proteolytic activity reduced the amount of VEGF bound to its receptor VEGFR2, impairing therefore one of the most important pathways that activates tumor angiogenesis. Finally, preliminary results have shown a reduction in the proliferation rate and in p16 levels, a tumor suppressor protein regulating the cell cycle, in the treatments with Ind1 or Saq1 combined with Rtv. Interestingly these data corroborate previous findings showing that Rtv affected the proteasome and therefore the cell cycle explaining the synergistic effects observed in our combinatorial treatments. In conclusion this work showed anti-tumor and anti-angiogenic effects of HIV-PIs on cervical carcinogenesis and identified the inhibition of MMPs activity as one of the main mechanisms of action of these compounds. Given their track records in clinical use with limited toxicity, these data suggest that HIV-PIs could represent new and safe drugs that can be used and added in combination with the conventional anti-tumor therapies used in clinic.