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CPBMF65, a synthetic human uridine phosphorylase-1 inhibitor, reduces HepG2 cell proliferation through cell cycle
Elisa Feller Gonçalves da Silva1, Kelly Goulart Lima1, Gabriele Catyana Krause1
1Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil.
Abstract:
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.
Insights
A novel compound, CPBMF65, inhibits human uridine phosphorylase-1 (hUP1), reducing hepatocellular carcinoma (HCC) cell proliferation. This hUP1 inhibitor effectively decreases HCC cell growth via cell cycle arrest and senescence.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with limited effective therapies.
- Uridine phosphorylase-1 (hUP1) regulates uridine (Urd) levels, a nucleoside involved in RNA synthesis and potentially modulating chemotherapy toxicity.
- Developing novel therapeutic strategies targeting HCC is crucial.
Purpose of the Study:
- To investigate the anti-proliferative effects of the synthetic compound CPBMF65, a potent hUP1 inhibitor, on the human hepatocellular carcinoma cell line (HepG2).
- To elucidate the mechanisms underlying CPBMF65's action, including its impact on cell cycle, apoptosis, senescence, autophagy, and intracellular Urd levels.
Main Methods:
- HepG2 cells were treated with CPBMF65.
- Analyses included cell proliferation, cytotoxicity, apoptosis, senescence, autophagy, intracellular Urd levels, cell cycle arrest, and drug resistance.
- Chronic treatment effects on cell proliferation were also assessed.
Main Results:
- CPBMF65 significantly decreased HepG2 cell proliferation.
- The primary mechanisms involved cell cycle arrest and induction of senescence.
- Intracellular Urd levels were increased, and reduced proliferation was sustained during chronic treatment.
Conclusions:
- CPBMF65, an hUP1 inhibitor, demonstrates significant anti-proliferative effects on HepG2 cells.
- This study is the first to show that CPBMF65 reduces HCC cell proliferation through cell cycle arrest and senescence.
- CPBMF65 presents a potential therapeutic strategy for HCC by targeting hUP1.
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