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CPBMF65, a synthetic human uridine phosphorylase-1 inhibitor, reduces HepG2 cell proliferation through cell cycle arrest and senescence

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Summary

Hepatocellular carcinoma (HCC) is the most prevalent type of tumor among primary liver tumors and is the second highest cause of cancer-related deaths worldwide. Current therapies are controversial, and more research is needed to identify effective treatments. A new synthetic compound, potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65), is a potent inhibitor of the human uridine phosphorylase-1 (hUP1) enzyme, which controls the cell concentration of uridine (Urd). Urd is a natural pyrimidine nucleoside involved in cellular processes, such as RNA synthesis. In addition, it is considered a promising biochemical modulator, as it may reduce the toxicity caused by chemotherapeutics without impairing its anti-tumor activity. Thus, the objective of this study is to evaluate the effects of CPBMF65 on the proliferation of the human hepatocellular carcinoma cell line (HepG2). Cell proliferation, cytotoxicity, apoptosis, senescence, autophagy, intracellular Urd levels, cell cycle arrest, and drug resistance were analyzed. Results demonstrate that, after incubation with CPBMF65, HepG2 cell proliferation decreased, mainly through cell cycle arrest and senescence, increasing the levels of intracellular Urd and maintaining cell proliferation reduced during chronic treatment. In conclusion, results show, for the first time, the ability of a hUP1 inhibitor (CPBMF65) to reduce HepG2 cell proliferation through cell cycle arrest and senescence.

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Funding

This study was financed, in part, by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasil. Finance Code 001.

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Authors and Affiliations

  1. Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil

    Elisa Feller Gonçalves da Silva, Kelly Goulart Lima, Gabriele Catyana Krause, Gabriela Viegas Haute, Leonardo Pedrazza, Bruno de Souza Basso, Henrique Bregolin Dias, Carolina Luft, Maria Claudia Rosa Garcia, Bruna Pasqualotto Costa, Géssica Luana Antunes, Márcio Vinícius Fagundes Donadio & Jarbas Rodrigues de Oliveira

  2. Laboratório de Biofísica Celular, Molecular e Computacional, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil

    Anderson Velasque Catarina

  3. Laboratório de Imunologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil

    Rodrigo Benedetti Gassen

  4. Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Tecnopuc, Porto Alegre, Rio Grande do Sul, Brazil

    Luiz Augusto Basso & Pablo Machado

Authors
  1. Elisa Feller Gonçalves da Silva
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  2. Kelly Goulart Lima
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  3. Gabriele Catyana Krause
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  9. Henrique Bregolin Dias
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  10. Carolina Luft
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  13. Géssica Luana Antunes
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  17. Jarbas Rodrigues de Oliveira
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Corresponding author

Correspondence to Géssica Luana Antunes.

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Conflict of interest

EFGS, KGL, GCK, GVH, LP, AVC, RBG, BSB, HBD, CL, MCRG, BPC, GLA, LAB, MVFD, PM, and JRO declare no conflicts of interest.

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da Silva, E.F.G., Lima, K.G., Krause, G.C. et al. CPBMF65, a synthetic human uridine phosphorylase-1 inhibitor, reduces HepG2 cell proliferation through cell cycle arrest and senescence. Invest New Drugs 38, 1653–1663 (2020). https://doi.org/10.1007/s10637-020-00941-2

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