Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells
Kirk Jensen1, Athanasios Bikas2, Aneeta Patel3
1Department of PediatricsUniformed Services University of the Health Sciences, Bethesda, Maryland, USA kirk.jensen@usuhs.edu.
Abstract:
The HIV protease inhibitor Nelfinavir (NFV) inhibits PI3K/AKT and MAPK/ERK signaling pathways, emerging targets in thyroid cancers. We examined the effects of NFV on cancer cells that derived from follicular (FTC), papillary (PTC) and anaplastic (ATC) thyroid cancers. NFV (1-20 µM) was tested in FTC133, BCPAP and SW1736 cell lines. The effects of NFV on cell proliferation were determined in vitro using real-time microscopy and by flow cytometry. DNA damage, apoptotic cell death and expression of molecular markers of epithelial-mesenchymal transition (EMT) were determined by Western blot and real-time PCR. Real-time imaging demonstrated that NFV (10 µM) increased the time required for the cell passage through the phases of cell cycle and induced DNA fragmentation. Growth inhibitory effects of NFV were associated with the accumulation of cells in G0/G1 phase, downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). NFV also induced the expression of γH2AX and p53BP1 indicating DNA damage. Treatment with NFV (20 µM) resulted in caspase-3 cleavage in all examined cells. NFV (20 µM) decreased the levels of total and p-AKT in PTEN-deficient FTC133 cells. NFV had no significant effects on total ERK and p-ERK in BRAF-positive BCPAP and SW1736 cells. NFV had no effects on the expression of EMT markers (Twist, Vimentin, E- and N-Cadherin), but inhibited the migration and decreased the abilities of thyroid cancer cells to survive in non-adherent conditions. We conclude that NFV inhibits proliferation and induces DNA damage in thyroid cancer cell lines. Our in vitro data suggest that NFV has a potential to become a new thyroid cancer therapeutic agent.
Insights
The HIV protease inhibitor Nelfinavir (NFV) inhibits thyroid cancer cell proliferation and induces DNA damage. NFV shows potential as a novel therapeutic agent for thyroid cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Thyroid cancers are a significant health concern with limited therapeutic options.
- Emerging research highlights the role of PI3K/AKT and MAPK/ERK signaling pathways in thyroid cancer progression.
- Nelfinavir (NFV), an HIV protease inhibitor, targets these pathways and presents a potential therapeutic avenue.
Purpose of the Study:
- To investigate the efficacy of Nelfinavir (NFV) against various thyroid cancer cell lines (follicular, papillary, and anaplastic).
- To elucidate the mechanisms underlying NFV's effects on thyroid cancer cell proliferation, cell cycle, DNA damage, and apoptosis.
- To assess NFV's impact on molecular markers of epithelial-mesenchymal transition (EMT) and cancer cell migration.
Main Methods:
- Utilized FTC133, BCPAP, and SW1736 thyroid cancer cell lines for in vitro studies.
- Assessed cell proliferation using real-time microscopy and flow cytometry.
- Determined DNA damage, apoptosis, and EMT marker expression via Western blot and real-time PCR.
Main Results:
- NFV treatment (10 µM) arrested the cell cycle, increased DNA fragmentation, and induced markers of DNA damage (γH2AX, p53BP1).
- NFV (20 µM) triggered caspase-3 cleavage, indicating apoptosis, and reduced AKT signaling in PTEN-deficient cells.
- NFV inhibited migration and survival in non-adherent conditions without affecting EMT markers.
Conclusions:
- Nelfinavir effectively inhibits proliferation and induces DNA damage in diverse thyroid cancer cell lines.
- NFV demonstrates potential as a novel therapeutic agent for thyroid cancer treatment.
- Further in vitro and in vivo studies are warranted to explore NFV's therapeutic potential.
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