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

• DOI: 10.1007/s10637-020-00941-2
• Publication Date: 2020-05-04T19:03:26Z
• Authors: Elisa Feller Gonç...; Kelly Goulart Lima; Gabriele Catyana ...; Gabriela Viegas H...; Leonardo Pedrazza; Anderson Velasque...; Rodrigo Benedetti...; Bruno de Souza Basso; Henrique Bregolin...; Carolina Luft; Maria Claudia Ros...; Bruna Pasqualotto...; Géssica Luana Ant...; Luiz Augusto Basso; Márcio Vinícius F...; Pablo Machado; Jarbas Rodrigues ...
• Keywords: Uridine Phosphorylase; 0303 health sciences; Carcinoma, Hepatocellular; Pyridines; Liver Neoplasms; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Hep G2 Cells; 3. Good health; 03 medical and health sciences; Drug Resistance, Neoplasm; Leukocytes, Mononuclear; Humans; Cisplatin; Uridine; Cellular Senescence; Cell Proliferation

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.