Age-Dependent Decrease in Hepatic Geranylgeranoic Acid Content in C3H/HeN Mice and Its Oral Supplementation Prevents Spontaneous Hepatoma

Abstract

Geranylgeranoic acid (GGA) has been developed as a preventive agent against second primary hepatoma. Recently, GGA was reported to induce cell death in human hepatoma cells via TLR4-mediated pyroptosis. We have reported that GGA is enzymatically biosynthesized from mevalonic acid in human hepatoma-derived cells and that endogenous GGA is found in most organs of rats. In addition, we found that upregulation of endogenous GGA levels by zaragozic acid A (ZAA) induced cell death in human hepatoma-derived cells. Therefore, we investigated the age-related changes in hepatic GGA and the possibility of suppressing hepatocarcinogenesis by GGA supplementation using male C3H/HeN mice that spontaneously develop hepatoma. We measured endogenous GGA and mRNA of MAOB, a key enzyme of GGA biosynthesis, in the liver of male C3H/HeN mice aged 6–93 weeks. We also tried suppressing spontaneous hepatocarcinogenesis by a single administration of GGA to C3H/HeN mice. Hepatic GGA content and Maob mRNA expression level age-dependently decreased in male C3H/HeN mice; some of which produced spontaneous hepatoma in 2 years. A single oral administration of GGA at 11 months of age significantly prevented hepatoma in terms of the number and weight of tumors per mouse at 24 months. Oral supplementation with GGA or geranylgeraniol significantly increased endogenous hepatic GGA contents dose-dependently; and ZAA dramatically upregulated hepatic GGA. In this study; we found an age-dependent decrease in hepatic endogenous GGA in male C3H/HeN mice and efficient prevention of spontaneous hepatoma by a single administration of GGA at 11 months of age.

Synergistic Effect of Squalene and Hydroxytyrosol on Highly Invasive MDA-MB-231 Breast Cancer Cells

“…HT is one of the main phenols present in VOO with interesting health benefits [11][12][13][14]. On the other hand, SQ, another important compound present in VOOs and olives, also has antitumor properties against several types of cancer, such as skin, breast and colon cancer [18][19][20][21][22][23][24]. Interestingly, both isolated compounds did not promote the inhibition of highly invasive breast cells in previous published works [17,26], but together at certain concentrations, appeared to promote the inhibition of breast cancer cells' growth and apoptosis, as well as increasing DNA damage.…”

“…Therefore, when squalene is ingested by diet, squalene-derived sterols accumulate in the cells and β-hydroxy-βmethylglutaryl-CoA reductase (HMG-CoA reductase) is inhibited [21]. Furthermore, recent evidence has shown that squalene excess leads to an accumulation of farnesyl pyrophosphate (FFP), which could be related to the suppression of carcinogenesis [22,23]. In fact, dietary ingestion of SQ can inhibit colon cancer development in vivo [24].…”

“…The bioprotective and antitumoral activities of VOO have been linked to its contents of minor compounds. Several studies remarked on different bioactivity properties of isolated VOO compounds [6,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26], but VOO's health-promoting properties could be attributed to synergistic effects of the nutrients present in it, such as minor compounds and fatty acids. HT and SQ are two of the minor compounds of VOO and both isolated compounds have been previously described to possess a preventive role in breast epithelial cells but without significant antitumoral activity in highly invasive breast cancer cells [17,26].…”

Hepatic CYP3A4 Enzyme Compensatively Maintains Endogenous Geranylgeranoic Acid Levels in MAOB-Knockout Human Hepatoma Cells

“…Finally, we would like to discuss the relationship between CYP3A4 enzyme and hepatoma from the viewpoint of inhibiting hepatocarcinogenesis, which is one of the biological activities of GGA. The liver normally expresses high levels of MAOB and biosynthesizes carcinogenic inhibitory GGA [7,12,31]. However, the enzymatic activity of MAOB is decreased at the site of hepatoma, and a classical paper described that the higher the grade of hepatoma, the lower the activity of MAOB [32].…”

Lifestyle and Hepatocellular Carcinoma What Is the Evidence and Prevention Recommendations

“…Cadmium, which is present in cigarettes, has been strongly associated with HCC [ 129 ]. Lastly, it has been shown that hepatic monoamine oxidase B (MAOB) is involved in the biosynthesis of geranylgeranoic acid (GGA) (found in animal models and hepatoma cell lines) which is believed to prevent hepatocarcinogenesis [ 130 , 131 ]. Nevertheless, smoking tobacco inhibits MABOB, which can lead to suppressing GGA and its preventive effect of hepatocarcinogenesis [ 132 ].…”