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

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.

Uridine phosphorylase‐1 promotes cell viability and cell‐cycle progression in human epidermal keratinocytes via the glycolytic pathway

“…Upregulation of UPP1 resulted in an increase in the volume of thyroid tumours, and downregulation of UPP1 suppressed the proliferation of thyroid cancer cell lines 24 . The same results were found for HepG2 cell proliferation subsequent to the use of a synthetic human UPP1 inhibitor 25 . Because the exact mechanism underpinning psoriasis remains unclear, crosstalk between keratinocytes and immunocytes is central to psoriasis.…”

“…According to previous studies, excessive keratinocyte proliferation contributes to the pathogenesis of psoriasis 1 . Moreover, UPP1 was found to be active in cancer cell lines and to facilitate cell proliferation 25 . These observations suggested a potential correlation between UPP1 and psoriasis.…”

“…1 Moreover, UPP1 was found to be active in cancer cell lines and to facilitate cell proliferation. 25 These observations suggested a potential correlation between UPP1 and psoriasis. Our bioinformatics analysis revealed that UPP1 mRNA was noticeably upregulated in lesion samples from psoriatic patients and this change was accompanied by activation of the IL-6/ STAT3 pathway and increased cell-cycle progression and glycolysis.…”

“…24 The same results were found for HepG2 cell proliferation subsequent to the use of a synthetic human UPP1 inhibitor. 25 Because the exact mechanism underpinning psoriasis remains unclear, crosstalk between keratinocytes and immunocytes is central to psoriasis. Multiple stimuli from cytokines may contribute to the rapid proliferation of keratinocytes, and massive proinflammatory cytokines or amplified inflammation are produced in response to growing keratinocytes through loop-like feedback.…”

UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT

“…In addition, CB-839 upregulated the expression of UPP1 in various transplantation tumor models, strengthening the inhibitory effect of 5-FU on PIK3CA-mutant colorectal cancer 63 . da Silva EFG et al demonstrated for the first time the ability of CPBMF65 to inhibit the proliferation of HepG2 cells by blocking the cell cycle and promoting cellular senescence 64 . Based on its in vitro antitumor activity and low toxicity in normal cells, CPBMF65 may be a candidate for future in vivo therapeutic studies in hepatocellular carcinoma.…”