Oxidative Stress Mediates the Antiproliferative Effects of Nelfinavir in Breast Cancer Cells.

Authors:
Maria Soprano
Maria Soprano
Federico II University
Napoli | Italy
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Maria Rosaria Rusciano
Maria Rosaria Rusciano
University of Naples Federico II
Italy
Angela Serena Maione
Angela Serena Maione
University of Naples Federico II
Italy
Gennaro Limite
Gennaro Limite
University of Naples Federico II
Italy
Pietro Forestieri
Pietro Forestieri
University of Naples Federico II
Italy

PLoS One 2016 9;11(6):e0155970. Epub 2016 Jun 9.

Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.

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.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155970PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900679PMC

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July 2017
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Mechanisms of endocrine resistance in breast cancer
CK Osborne et al.
Annu Rev Med 2011
The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells
F Pajonk et al.
Cancer Res 2002

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