Inhibition of Spontaneous Hepatocarcinogenesis by 4,5-Didehydrogeranylgeranoic Acid: Effects of Small-Dose and Infrequent Administration

Abstract

Inhibitory effects of 4,5-didehydrogeranylgeranoic acid (dGGA) on the development of tumors were investigated in spontaneous hepatoma mice, C3H/HeNCrj. Experiment 1: Male mice at 8 weeks of age were raised on a basal diet, and then provided with a diet containing 0.02% dGGA from 32 to 91 weeks of age. Experiment 2: dGGA was administered to the animals only once at different time points, from 2 months to 17 months after birth, respectively. Experiment 3: dGGA was administered twice to the mice at different time points: at 5 months and 11 months, and at 8 months and 11 months, respectively. When the inhibitory effects on tumor development were evaluated with the incidences of tumors, average numbers, and weight of tumors per mouse, there was a marked relationship between the time of single or dual dosing and the inhibitory effects of dGGA. The greatest inhibitory effects were observed in Experiment 3 in the group of animals given dGGA at the ages of 8 and 11 months, which were far superior to the results with a large dose of the compounds for a long time. These results might indicate that dGGA administered at the right time in the right amount effectively prevents the development of cancer.

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

“…By this time, almost all mice can be detected with spontaneous liver cancer [87,88]. However, when GGA or 4,5-didehydroGGA is administered orally as a single dose (50 µg/mouse) at 11-12 months of age, the detection rate of liver cancer at 24 months of age is significantly suppressed [86,88]. Since tumors are observed in the liver of C3H/HeN male mice from the first year of life {87}, it is conceivable that GGA administered at this time induces pyroptotic cell death in tumor cells, sweeping them away from the liver.…”

“…In C3H/HeN male mice, liver GGA content begins to decrease from 7 months of age, decreases further by around 15 months of age, and becomes undetectable by 23 months of age [86]. By this time, almost all mice can be detected with spontaneous liver cancer [87,88]. However, when GGA or 4,5-didehydroGGA is administered orally as a single dose (50 µg/mouse) at 11-12 months of age, the detection rate of liver cancer at 24 months of age is significantly suppressed [86,88].…”

Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

“…By this time, almost all mice can be detected with spontaneous liver cancer [89,90]. However, when GGA or 4,5-didehydroGGA is administered orally as a single dose (50 µg/mouse) at 11-12 months of age, the detection rate of liver cancer at 24 months of age is significantly suppressed [88,90]. Since tumors are observed in the liver of C3H/HeN male mice from the first year of life [89], it is conceivable that GGA administered at this time induces pyroptotic cell death in tumor cells, sweeping them away from the liver.…”

“…In C3H/HeN male mice, the liver GGA content begins to decrease from 7 months of age, decreases further by around 15 months of age, and becomes undetectable by 23 months of age [88]. By this time, almost all mice can be detected with spontaneous liver cancer [89,90]. However, when GGA or 4,5-didehydroGGA is administered orally as a single dose (50 µg/mouse) at 11-12 months of age, the detection rate of liver cancer at 24 months of age is significantly suppressed [88,90].…”