The discovery of the anti-proliferative activity of
nelfinavir in HIV-free models has encouraged its investigation as anticancer
drug. Although the molecular mechanism by which
nelfinavir exerts antitumor activity is still unknown, its effects have been related to Akt inhibition. Here we tested the effects of
nelfinavir on cell proliferation, viability and death in two human
breast cancer cell lines and in human normal primary breast cells. To identify the mechanism of action of
nelfinavir in
breast cancer, we evaluated the involvement of the Akt pathway as well as the effects of
nelfinavir on
reactive oxygen species (ROS) production and ROS-related
enzymes activities.
Nelfinavir reduced
breast cancer cell viability by inducing apoptosis and
necrosis, without affecting primary normal breast cells. The antitumor activity of
nelfinavir was related to alterations of the cell redox state, coupled with an increase of intracellular ROS production limited to
cancer cells.
Nelfinavir treated
tumor cells also displayed a downregulation of the Akt pathway due to disruption of the Akt-HSP90 complex, and subsequent degradation of Akt. These effects resulted to be ROS dependent, suggesting that ROS production is the primary step of
nelfinavir anticancer activity. The analysis of ROS-producers and ROS-detoxifying
enzymes revealed that
nelfinavir-mediated ROS production was strictly linked to flavoenzymes activation. We demonstrated that ROS enhancement represents the main molecular mechanism required to induce cell death by
nelfinavir in
breast cancer cells, thus supporting the development of new and more potent oxidizing molecules for
breast cancer therapy.