Synergic effect of OP449 and FTY720 on oral squamous cell carcinoma

Author(s)

Goto, Renata Nishida ^[1] ; Sobral, Lays Martin ^[1] ; Stringhetta-Padovani, Karina ^[1] ; Garcia, Cristiana B. ^[1] ; da Silva, Gabriel ^[1] ; Vitek, Michael P. ^[2] ; Leopoldino, Andreia Machado ^{[1, 3]}

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Sci, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Oncotides Pharmaceut, Durham, NC - USA

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Reg Blood Ctr Ribeirao Preto, CEPID CTC, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 882, SEP 5 2020.
• Web of Science Citations: 0

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 anti-tumoral 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 mu M OP449 in combination with 15 mu M 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 NF kappa B signaling as targets for OSCC therapy. (AU)

• FAPESP's process: 13/00374-8 - Analysis of hnRNPK protein in cell lines NB4 and NB4-R2 of acute myeloid leukemia with emphasis in pathogenesis and cell differentiation by all-trans retinoic acid
• Grantee: Karina Stringhetta Padovani
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/01355-7 - In vitro and in vivo study of new compounds: with target-specific (hnRNP K) or action in the mitochondria for use as antitumor oral carcinoma or as cytoprotective in non-tumor cell
• Grantee: Renata Nishida Goto
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/10898-4 - Study of the molecular mechanisms by protein SET with impact on tumorigenesis and progression of oral cancer
• Grantee: Carlos Curti
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/17480-9 - Study of SET and sphingolipids in head and neck cancer: signaling, targets and antitumor therapy
• Grantee: Gabriel da Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/19103-2 - SET and sphingolipids in head and neck squamous cell carcinoma: signaling, targets and antiumoral therapy
• Grantee: Andréia Machado Leopoldino
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC