Inhibitory effects of synthetic acidic retinoid and polyprenoic acid on the development of hepatoma in rats induced by 3′-methyl-N, N-dimethyl-4-aminoazobenzene

Abstract

A study was conducted to investigate the inhibitory effects of acidic retinoid (trimethylmethoxyphenyl analog of retinoic acid ethylester or TMMP) and polyprenoic acid (3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid or E-5166) on the development of hepatoma induced by 3'-methyl-N, N-dimethyl-4-aminoazobenzene (3'-MeDAB) in rats. Morphometric analysis of liver specimens was employed to evaluate the antitumor effects of the compounds in detail, and revealed significant decreases in the number and area of tumors in the TMMP- and E-5166-treated groups. As for adverse effects, retarded growth and marked hypertriglyceridemia were observed only in TMMP-treated rats. During the hepatocarcinogenesis, cellular retinoid-binding protein, F-type or CRBP(F) and cellular retinoic acid-binding protein or CRABP newly appeared in the tumor tissue, particularly in hyperplastic nodules which are the precancerous state of hepatoma. These results suggest that the polyprenoic acid is a good candidate for clinical chemoprevention of hepatoma, targetting its precancerous stage when intracellular receptors for acidic retinoid have emerged.

Geranylgeraniol oxidase activity involved in oxidative formation of geranylgeranoic acid in human hepatoma cells

“…GGA and its derivatives were historically developed as synthetic "acyclic retinoids" by screening for their ability to bind to cellular retinoic acid-binding protein (13), and to nuclear retinoid receptors (1), which transcriptionally activate certain hepatocyte-specific genes in hepatoma cells (26). While GGA is generally considered to be a synthetic compound, its chemical structure suggests that GGA occurs as a natural substance in a group of acyclic terpenoids.…”

<b>Upregulation of energy metabolism-related, p53-target TIGAR and SCO2 in HuH-7 cells with p53 mutation by geranylgeranoic acid tr</b><b>eatment </b>

“…And we recently reported a possible mechanism that GGA could be biosynthesized from mevalonate pathway even in mammalian cells (15). In the past two decades, 4,5-didehydroGGA has been proven to suppress carcinogenesis in experimental animals (17), and to be an efficient chemical to prevent post-operative patients against second primary hepatoma in a phase II clinical trial (18,20), which has recently been further confirmed in a multicenter, randomized, double-blind, placebocontrolled study with a dose-dependent manner (23,24). GGA and 4,5-didehydroGGA were initially screened as acyclic retinoids to bind to the cellular retinoic acid-binding protein (19).…”

Retinoids and Cancer Chemoprevention

“…CHEMOPREVENTION OF HEPATOMA WITH RETINOIDS Supplementation with several natural or synthetic retinoids inhibits the development of experimental hepatoma [4]. Among these retinoids, E5166 was found to inhibit the development of hepatoma in both spontaneous hepatoma bearing mouse (C3H/HeNCrj) (TABLE 3) and 31-methyl-N, N-dimethy1-4-aminoazobenzene treated rats [12,13]. In addition, E5166 showed no adverse effect while similarly effective trimethyl methoxyphenyl (TMMP) analog of retinoic acid ethylester gave growth retardation and hypertriglyceridemia in the same experiment [13].…”

“…Among these retinoids, E5166 was found to inhibit the development of hepatoma in both spontaneous hepatoma bearing mouse (C3H/HeNCrj) (TABLE 3) and 31-methyl-N, N-dimethy1-4-aminoazobenzene treated rats [12,13]. In addition, E5166 showed no adverse effect while similarly effective trimethyl methoxyphenyl (TMMP) analog of retinoic acid ethylester gave growth retardation and hypertriglyceridemia in the same experiment [13]. Thus, E5166 is currently regarded as one of the most effective and less-toxic synthetic compounds on the basis of animal experiment.…”