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Oxidative stress mediates the antiproliferative effects of nelfinavir in breast cancer cells
- Source :
- PLoS ONE, Vol 11, Iss 6, p e0155970 (2016), PLoS ONE, PloS one 11 (2016). doi:10.1371/journal.pone.0155970, info:cnr-pdr/source/autori:Soprano M.; Sorriento D.; Rusciano M.R.; Maione A.S.; Limite G.; Forestieri P.; D'Angelo D.; D'Alessio M.; Campiglia P.; Formisano P.; Iaccarino G.; Bianco R.; Illario M./titolo:Oxidative stress mediates the antiproliferative effects of nelfinavir in breast cancer cells/doi:10.1371%2Fjournal.pone.0155970/rivista:PloS one/anno:2016/pagina_da:/pagina_a:/intervallo_pagine:/volume:11
- Publication Year :
- 2016
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cell
Cancer Treatment
Organic chemistry
lcsh:Medicine
Apoptosis
Pharmacology
Pathology and Laboratory Medicine
Epithelium
0302 clinical medicine
Animal Cells
immune system diseases
Breast Tumors
Tumor Cells, Cultured
Medicine and Health Sciences
Vitamin E
Cell Cycle and Cell Division
lcsh:Science
Nelfinavir
Multidisciplinary
Oxidative Stress Mediates
Cancer
Cells
Cell Death
Medicine (all)
virus diseases
Vitamins
Physical sciences
Chemistry
medicine.anatomical_structure
Oncology
Cell Processes
030220 oncology & carcinogenesis
Female
Cellular Types
Anatomy
Research Article
medicine.drug
Programmed cell death
Antineoplastic Agents
Breast Neoplasms
Biology
Chemical compounds
Necrosis
03 medical and health sciences
Signs and Symptoms
Diagnostic Medicine
Cyclins
Breast Cancer
Organic compounds
medicine
Humans
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Biochemistry, Genetics and Molecular Biology (all)
Cell growth
lcsh:R
Cancers and Neoplasms
Biology and Life Sciences
Epithelial Cells
HIV Protease Inhibitors
Cell Biology
biochemical phenomena, metabolism, and nutrition
Oxidative Stress
Biological Tissue
030104 developmental biology
Agricultural and Biological Sciences (all)
Cancer cell
lcsh:Q
Reactive Oxygen Species
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- PLoS ONE, Vol 11, Iss 6, p e0155970 (2016), PLoS ONE, PloS one 11 (2016). doi:10.1371/journal.pone.0155970, info:cnr-pdr/source/autori:Soprano M.; Sorriento D.; Rusciano M.R.; Maione A.S.; Limite G.; Forestieri P.; D'Angelo D.; D'Alessio M.; Campiglia P.; Formisano P.; Iaccarino G.; Bianco R.; Illario M./titolo:Oxidative stress mediates the antiproliferative effects of nelfinavir in breast cancer cells/doi:10.1371%2Fjournal.pone.0155970/rivista:PloS one/anno:2016/pagina_da:/pagina_a:/intervallo_pagine:/volume:11
- Accession number :
- edsair.doi.dedup.....f6e0f1264aaeff0b23ee68a69fa85f2e