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 monoamine oxidase (BMAOB), 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.
Highlights
Introduction iationsGeranylgeranoic acid and its didehydro derivative have been developed as preventive agents against second primary hepatoma [1,2]
Endogenous GGA levels in C3H/HeN mouse liver began to decrease after 20 weeks of age and remained significantly low from 25 to 60 weeks of age, and declined rapidly until hepatic GGA became completely undetectable at 93 weeks of age (Figure 2A)
The GGA level in the liver increased by zaragozic acid A (ZAA) returned to the initial level after 12 h of administration (Figure 6C)
Summary
Geranylgeranoic acid (all-trans 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid or GGA) and its didehydro derivative (all-trans 3,7,11,15-tetramethyl-2,4,6,10,14hexadecapentaenoic acid or peretinoin) have been developed as preventive agents against second primary hepatoma [1,2]. The 4,5-didehydro derivative of GGA potentially prevented second primary hepatoma in placebo-controlled randomized phase II/III clinical trials [3,4]. Using some human hepatoma-derived cell lines, we found that both GGA and 4,5-didehydroGGA induced tumor-specific cell death, which may be involved in the suppression of second primary hepatocarcinogenesis [5,6]. As for the molecular and cellular mechanisms of GGA-induced cell death, several studies have so far been conducted.
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