Oxidative Stress Mediates the Antiproliferative Effects of Nelfinavir in Breast Cancer Cells.
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.
Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
Maria
M
Soprano
Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples, Italy.
Daniela
D
Sorriento
Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
Maria Rosaria
MR
Rusciano
Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
Angela Serena
AS
Maione
Department of Clinical Medicine and Surgery, Breast Unit, University of Naples Federico II, Naples, Italy.
Gennaro
G
Limite
Department of Clinical Medicine and Surgery, Breast Unit, University of Naples Federico II, Naples, Italy.
Pietro
P
Forestieri
Department of Emergency and Reception, Plastic Surgery Operative Unit, Hospital Center A. Cardarelli, Naples, Italy.
Dario
D
D'Angelo
Department of Emergency and Reception, Plastic Surgery Operative Unit, Hospital Center A. Cardarelli, Naples, Italy.
Matteo
M
D'Alessio
Department of Pharmacy, University of Salerno, Salerno, Italy.
Pietro
P
Campiglia
Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
Pietro
P
Formisano
Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
Guido
G
Iaccarino
Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.
Roberto
R
Bianco
Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
Maddalena
http://orcid.org/0000-0001-9834-6517
M
Illario
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017320:HIV Protease Inhibitors; D017382:Reactive Oxygen Species; D019888:Nelfinavir