Synergic effect of OP449 and FTY720 on oral squamous cell carcinoma

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 882, SEP 5 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 13/00374-8 - Análise da proteína hnRNPK nas linhagens celulares NB4 e NB4-R2 de leucemia promielocítica aguda com ênfase na patogênese e na diferenciação celular pelo ácido all-trans retinóico
• Beneficiário: Karina Stringhetta Padovani
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/01355-7 - Estudo in vitro e in vivo de novos compostos: com alvo-específico (hnRNP K) ou com ação na mitocôndria para uso como antitumoral em carcinoma oral ou como citoprotetor em célula não-tumoral
• Beneficiário: Renata Nishida Goto
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/10898-4 - Estudo dos mecanismos moleculares associados à proteína SET com impacto na tumorigênese e progressão do câncer oral
• Beneficiário: Carlos Curti
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/17480-9 - Estudo da SET e esfingolipídeos em câncer de cabeça e pescoço: sinalização, alvos e terapia antitumoral
• Beneficiário: Gabriel da Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/19103-2 - SET e esfingolipídeos em câncer de cabeça e pescoço: sinalização, alvos e terapia antitumoral
• Beneficiário: Andréia Machado Leopoldino
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs