Combinatorial antitumor effects of amino acids and epigenetic modulations in hepatocellular carcinoma cell lines

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2021-11, Vol.394 (11), p.2245-2257
• Main Authors: Hassan, Yasmine A., Helmy, Maged W., Ghoneim, Asser I.
• Format: Article
• Language: English
• Subjects: Amino acids; Amino Acids - administration & dosage; Amino Acids - pharmacology; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Caspase 3 - metabolism; Caspase-3; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Cyclin D1; Dose-Response Relationship, Drug; Enzyme-linked immunosorbent assay; Epigenesis, Genetic; Epigenetics; Glutamine; Hep G2 Cells; Hepatocellular carcinoma; Histone deacetylase; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - pharmacology; Humans; Insulin; Insulin-like growth factor I; Kinases; Leucine; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Methionine; Neurosciences; Original Article; p53 Protein; Pharmacology/Toxicology; Ribosomal protein S6; Ribosomal protein S6 kinase; Signal Transduction - drug effects; Supplements; Tumor cell lines; Tumor Suppressor Protein p53 - metabolism; Vorinostat - administration & dosage; Vorinostat - pharmacology
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-021-02140-z

Hepatocellular carcinoma (HCC) is a highly fatal form of liver cancer. Recently, the interest in using amino acids as therapeutic agents has noticeably grown. The present work aimed to evaluate the possible antiproliferative effects of selected amino acids supplementation or deprivation in human HCC cell lines and to investigate their effects on critical signaling molecules in HCC pathogenesis and the outcomes of their combination with the histone deacetylase inhibitor vorinostat. HepG2 and Huh7 cells were treated with different concentrations of l -leucine, l -glutamine, or l -methionine and cell viability was determined using MTT assay. Insulin-like growth factor 1 (IGF1), phosphorylated ribosomal protein S6 kinase (p70 S6K), p53, and cyclin D1 (CD1) protein levels were assayed using ELISA. Caspase-3 activity was assessed colorimetrically. l -leucine supplementation (0.8–102.4 mM) and l -glutamine supplementation (4–128 mM) showed dose-dependent antiproliferative effects in both cell lines but l -methionine supplementation (0.2–25.6 mM) only affected the viability of HepG2 cells. Glutamine or methionine deprivation suppressed the proliferation of HepG2 cells whereas leucine deprivation had no effect on cell viability in both cell lines. The combination between the effective antiproliferative changes in l -leucine, l -glutamine, and l -methionine concentrations greatly suppressed cell viability and increased the sensitivity to vorinostat in both cell lines. The growth inhibitory effects were paralleled with significant decreases in IGF-1, phospho p70 S6k, and CD1 levels and significant elevations in p53 and caspase-3 activity. Changes in amino acids concentrations could profoundly affect growth in HCC cell lines and their response to epigenetic therapy.