Journal
TUMOR BIOLOGY
Volume 37, Issue 10, Pages 14259-14269Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1007/s13277-016-5290-9
Keywords
Epithelial ovarian cancer; Sp1; Survivin; Cisplatin; Tolfenamic acid
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Funding
- Ovarian Cancer Alliance of Florida
- Institute for Cancer Research and Pre-clinical Services, UNTHSC
- Florida Hospital Gala Endowed Program for Oncologic Research
- National Institute on Minority Health and Health Disparities, NIH [1P20 MD006882]
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The expression of specificity protein 1 (Sp1) and survivin was evaluated in clinical specimens of epithelial ovarian cancer (EOC) patients. When compared to normal tissue, EOC samples showed high expression of Sp1 and survivin using qPCR (Sp1: similar to 2-fold; survivin: similar to 5-fold) and Western blot (Sp1: > 2.6-fold; survivin: > 100-fold). The Sp1 inhibitor, and anti-cancer small molecule, tolfenamic acid (TA), was tested to enhance the response of Cisplatin (Cis) in EOC cell lines. Cell viability (CellTiter-Glo), combination index (CalcuSyn software), apoptosis (Annexin-V staining), cell cycle analyses (flow cytometry), and reactive oxygen species (flow cytometry) were determined. Cell migration and invasion was assessed using matrigel coated transwell chambers. Agilent Technologies proteomics analysis identified potential signaling pathways involved. The combination of TA (50 mu M) and Cis (5 mu M) synergistically increased the growth inhibition in ES2 (similar to 80 %, p < 0.001) and OVCAR-3 (60 %, p < 0.001) cells. TA or TA + Cis treatment in ES2 cells caused cell cycle arrest in G1 Phase (TA) or S-Phase (TA + Cis) and unregulated reactive oxygen species. Invasion and migration was decreased in ES2 cells. Global proteomic profiling showed modulation of proteins associated with oxidative phosphorylation, apoptosis, electron transport chain, DNA damage, and cell cycle proteins. These results demonstrate an association of Sp1 and survivin in EOC and confirm targeting these candidates with TA potentially sensitizes EOC cells to cisplatin.
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