S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 3; p. 409
• Main Authors: Pascale, Rosa M, Simile, Maria M, Calvisi, Diego F, Feo, Claudio F, Feo, Francesco
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.01.2022; MDPI
• Subjects: 5-aza-2'-deoxycytidine; Acetaminophen; Adenosylmethionine; alcoholic liver disease; Animal models; Animals; Antitumor activity; Antiviral Agents - therapeutic use; Apoptosis; Betaine; Binding sites; Breast cancer; Carbon tetrachloride; Carcinogenesis; Carcinoma, Hepatocellular - pathology; Cell growth; Cell proliferation; Cell Transformation, Neoplastic; Cholestasis; Cirrhosis; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; D-Galactosamine; DNA methylation; Doxorubicin; Ethanol; Fatty liver; Gemcitabine; Gene expression; Hepatitis; Hepatocellular carcinoma; Hepatocytes; Homocysteine; Humans; Interferon; intra-hepatic cholestasis; Kinases; Liver cancer; Liver cirrhosis; Liver diseases; Liver Neoplasms - pathology; Male; Metabolism; Methionine; Methionine Adenosyltransferase; methionine cycle; non-alcoholic fatty liver; Non-alcoholic Fatty Liver Disease - drug therapy; Physiology; Polyamines; Proteins; Rats; Review; Ribavirin - therapeutic use; S-adenosyl-L-methionine; S-Adenosylmethionine - metabolism; S-Adenosylmethionine - pharmacology; S-Adenosylmethionine - therapeutic use; viral hepatitis; Vitamin B; Vitamin E; methionine cycle; viral hepatitis; alcoholic liver disease; non-alcoholic fatty liver; S-adenosyl-L-methionine; intra-hepatic cholestasis
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11030409

Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.