Abstract
The aim of this study was to investigate the antitumor activities of Phyllanthus amarus (PHA) and its potential of herb–drug interactions with 5-Fluorouracil (5-FU). Cell viability, ribonucleotides (RNs) and deoxyribonucleotides (dRNs) levels, cell cycle distribution, and expression of thymidylate synthase (TS) and ribonucleotide reductase (RR) proteins were measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) method, flow cytometry and Western blot analysis, respectively. Our standardized PHA extract showed toxicity to HepG2 cells at high concentrations after 72 h exposure and induced G2/M cell cycle arrest. Combined use of 5-FU with PHA resulted in significant decreases in ATP, CTP, GTP, UTP and dTTP levels, while AMP, CMP, GMP and dUMP levels increased significantly compared with use of 5-FU alone. Further, PHA could increase the role of cell cycle arrest at S phase induced by 5-FU. Although PHA alone had no direct impact on TS and RR, PHA could change the levels of RNs and dRNs when combined with 5-FU. This may be due to cell cycle arrest or regulation of key enzyme steps in intracellular RNs and dRNs metabolism.
Highlights
Nucleoside analogs (NAs) have been developed for almost 50 years for treating cancers or viral infections [1]
5-fluoro-20 -deoxyuridine-50 -monophosphate (FdUMP), is an irreversible inhibitor of thymidylate synthase (TS), 5-FU incubation could lead to decrease of intracellular deoxythymidine triphosphate and increase of deoxyuridine monophosphate [9,10]
Corilagin has been used as a marker compound, it seems to be insufficient to assess the quality of Phyllanthus [22]
Summary
Nucleoside analogs (NAs) have been developed for almost 50 years for treating cancers or viral infections [1]. NAs usually produce their major therapeutic effects through inhibition of DNA and RNA synthesis, regulation of key intracellular enzymes, and interference with cell signaling and intracellular metabolisms. These action mechanisms inevitably affect the natural ribonucleotides (RNs) and deoxyribonucleotides (dRNs) pool sizes, which play important roles in broad cellular functions such as DNA replication, proliferation and cell cycling [2,3]. 5-fluoro-20 -deoxyuridine-50 -monophosphate (FdUMP), is an irreversible inhibitor of thymidylate synthase (TS), 5-FU incubation could lead to decrease of intracellular deoxythymidine triphosphate (dTTP) and increase of deoxyuridine monophosphate (dUMP) [9,10].
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