S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model

Abstract

Hepatocellular carcinoma (HCC) remains a common cancer worldwide that lacks effective chemoprevention or treatment. Chronic liver disease often leads to impaired hepatic Sadenosylmethionine (SAMe) biosynthesis, and mice with SAMe deficiency develop HCC spontaneously. SAMe is antiapoptotic in normal hepatocytes but proapoptotic in cancerous hepatocytes. The present study investigated SAMe's effectiveness in prevention and treatment of HCC. Two weeks after injecting 2.5 million H4IIE cells into the liver parenchyma of ACI rats, they typically form a 1-cm tumor. When SAMe (150 mg/kg/day) was delivered through continuous intravenous infusion, hepatic SAMe levels reached 0.7 mM (over 10-fold) 24 hours later. This regimen, started 1 day after injecting H4IIE cells and continued for 10 days, was able to reduce tumor establishment and growth. However, if intravenous SAMe was started after HCC had already developed, it was ineffective in reducing tumor growth for 24 days. Although plasma SAMe levels remained elevated, hepatic SAMe levels were minimally increased (30% higher). Chronic SAMe administration led to induction of hepatic methyltransferases, which prevented SAMe accumulation. To see if SAMe's preventive effect on tumor establishment involves angiogenesis, the effect of SAMe on angiogenesis genes was studied. SAMe treatment of H4IIE cells altered the expression of several genes with the net effect of inhibiting angiogenesis. These changes were confirmed at the protein level and functionally in human umbilical vein endothelial cells. Conclusion: SAMe is effective in preventing HCC establishment but ineffective in treating established HCC because of induction of hepatic methyltransferases, which prevents SAMe level to reach high enough to kill liver cancer cells. SAMe's chemopreventive effect may be related to its proapoptotic action and its ability to inhibit angiogenesis. (HEPATOLOGY 2009;50:462-471.) H epatocellular carcinoma (HCC) is the fifth most common cancer and the third most frequent cause of cancer death worldwide. 1 The incidence of HCC is expected to rise due to the high prevalence of chronic hepatitis C in many parts of the world. 2 Only 30% of HCC patients are considered candidates for surgical resection, and the overall 5-year survival for HCC patients is less than 10%. 3 Treatments for advanced HCC

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…Enriched abundance of SAM inhibited the growth of breast cancer,80 liver cancer,81, 82 colon cancer83 and gastric cancer cells 84…”

N6‐methyladenosine modification in mRNA: machinery, function and implications for health and diseases

“…Increasing levels of SAM, the donor of the methyl group in m 6 A methylation reactions, inhibit the growth of breast cancer [139], liver cancer [140,141], colon cancer [142] and gastric cancer cells. Furthermore, the inhibitory effect on gastric cancer was shown to be accompanied by low mRNA and protein levels of c-myc and urokinase plasminogen activator [143].…”

MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma

“…The dominant mechanism of SAMe chemopreventive effect was thought to be from preventing hypomethylation of the promoter region of several protooncogenes, as SAMe's chemopreventive effect was blocked by 5-azacytidine (9,10). However, in an orthotopic liver cancer model, SAMe administration was also able to inhibit HCC establishment but was ineffective in blocking growth of already existing HCC (11). Part of this was because of a compensatory response of the liver to induce methyltransferases that removed excess SAMe to prevent its accumulation (11).…”