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Synergic effect of OP449 and FTY720 on oral squamous cell carcinoma
Renata Nishida Goto1, Lays Martin Sobral1, Karina Stringhetta-Padovani1
1Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
Abstract:
As SET protein is overexpressed and PP2A activity is reduced in oral squamous cell carcinoma (OSCC), this study aimed to assess the effects induced by OP449, a PP2A activator/SET inhibitor, on OSCC cells in vitro, and its potential either isolated or combined with FTY720, a PP2A activator/sphingosine kinase 1 antagonist, as antitumoral therapy in vivo. SET protein was analyzed in cells by immunoblotting and cancer stem cells by aldehyde dehydrogenase 1 assay (ALDH1). The cytotoxicity of OP449 was determined in five OSCC lineages by resazurin assay. Molecular actions of OP449 in SET targets were determined by immunoblotting. The coefficient of drug interaction (CDI) was used to characterize the synergism of OP449 and FTY720. The xenograft HN12 tumor model in nude mice was used to assess the antitumoral effect of OP449 and/or FTY720. HN12 (metastatic) cells showed higher SET and ALDH1 levels, and together with SCC9 cells were selected for molecular analysis. OP449 altered several SET functions/targets, such as histone H3 acetylation and NFkB. A synergism in cytotoxicity was observed when HN12 and SCC9 cells were pre-treated with 2 μM OP449 in combination with 15 μM FTY720 (CDI = 0.27 ± 0.088). Nude mice bearing xenograft HN12 tumors treated with OP449 and FTY720 showed reduced tumor mass. Moreover, NFkB was reduced in tumors after treatment. OP449 targets several SET functions, not only PP2A inhibition. Besides, OP449 plus FTY720 has a synergistic antitumoral effect on OSCC. Our results suggest new combined therapies and highlight SET and NFκB signaling as targets for OSCC therapy.
Insights
The study found that OP449 and FTY720 synergistically inhibit oral squamous cell carcinoma (OSCC) growth by targeting SET protein and NF-kB signaling. This combined therapy shows promise for OSCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Oral squamous cell carcinoma (OSCC) exhibits overexpression of SET protein and reduced PP2A activity.
- SET protein and aldehyde dehydrogenase 1 (ALDH1) levels are elevated in metastatic OSCC cells.
Purpose of the Study:
- To evaluate the in vitro effects of OP449, a PP2A activator/SET inhibitor, on OSCC cells.
- To assess the in vivo antitumoral potential of OP449, alone or combined with FTY720 (a PP2A activator/sphingosine kinase 1 antagonist), in an OSCC xenograft model.
Main Methods:
- Cytotoxicity was assessed using the resazurin assay in five OSCC cell lines.
- Molecular targets of OP449, including histone H3 acetylation and NF-kB, were analyzed by immunoblotting.
- Synergism between OP449 and FTY720 was determined using the coefficient of drug interaction (CDI) and evaluated in vivo using a xenograft HN12 tumor model.
Main Results:
- OP449 demonstrated cytotoxicity against OSCC cells and modulated SET protein functions, including histone H3 acetylation and NF-kB.
- A synergistic cytotoxic effect was observed when HN12 and SCC9 cells were pre-treated with OP449 and FTY720 (CDI = 0.27 ± 0.088).
- Combined treatment with OP449 and FTY720 significantly reduced tumor mass in vivo and decreased NF-kB levels in tumors.
Conclusions:
- OP449 targets multiple SET protein functions beyond PP2A inhibition.
- The combination of OP449 and FTY720 exhibits synergistic antitumoral activity against OSCC.
- Targeting SET protein and NF-kB signaling presents a promising therapeutic strategy for OSCC.
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