Study of anti-tumoral activity of HIV-Protease Inhibitor nelfinavir and identification of new nelfinavir-derivative compounds

Human Immunodeficiency Virus-Protease Inhibitors (HIV-PIs) are peptidomimetic drugs used in AIDS therapy to inhibit HIV infection by blocking viral protease. The advent of these drugs has led to a reduced incidence of HIV-associated tumors, particularly Kaposi’s sarcoma, non-Hodgkin’s lymphoma and cervical cancer. Many studies have also reported an anti-proliferative non-virological action of HIV-PIs in HIV-free models leading them to be further investigated as anti-cancer drugs. In particular HIV-PIs affect several pathways involved in tumor-cell proliferation and survival, angiogenesis, invasion, inflammation, and antitumor immunity in HIV-free models. The most effective anti-cancer HIV-PIs is nelfinavir, that is in clinical trial for several tumor types, thus encouraging the study of the intracellular pathways at the basis of their anti-tumor activity. The anti-tumoral effects of nelfinavir have been related to inhibition of Akt activation, but to date the molecular mechanism at the basis of anti-cancer activity in breast cancer is poorly understood. My results suggest an anti-proliferative activity of nelfinavir in a panel of cancer cell lines. In particular, nelfinavir induces apoptosis and necrosis in breast cancer cell lines such as MDA-MB231 and MCF-7 cells by affecting cell cycle in a cell line dependent way. The anti-tumor activity of nelfinavir is linked to the perturbation of cellular redox state; resulting in an increase of intracellular reactive oxygen species (ROS) production in breast cancer cells but not in normal breast epithelial cells. Nelfinavir treated tumor cells show also a downregulation of akt pathway due to the disruption of akt-Heat Shock Protein 90 kDa (HSP90) complex that is induced by nelfinavir and subsequent degradation of akt via proteasome. These effects result to be ROS dependent. Since treatment with anti-oxidant free radical scavenger tocopherol restores akt expression levels as well as viability of nelfinavir-untrated cells, the increase of ROS production represents the main and necessary molecular mechanism to induce cell death in breast cancer cell lines. The anti-cancer effectiveness of nelfinavir has motivated its use as lead compound in this study to design novel anti-tumoral compounds. Primary screening has led to the identification of novel nelfinavir-derivative (4n) with a high anti-cancer efficacy (IC50 50nM), that is a promising molecule to further evaluate for cancer therapy