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Triterpenoids


 

Triterpenoids, to which squalene is the immediate biologic precursor, include steroids and, thus, sterols, and represent the largest group of terpenoids, the most abundant group of botanical constituents and the most common ingredient class found in volatile oils. Consequently, triterpenoids appear in numerous botanical products with traditional and modern applications to dermatology, such as Centella asiatica (gotu kola) and propolis.

Indeed, the naturally occurring triterpenoids, oleanolic acid and ursolic acid, are known to confer anticarcinogenic and anti-inflammatory effects in certain cells (Exp. Dermatol. 2006;15:66–73). Ursolic acid and the natural triterpenoid erythrodiol have also been found to be effective in a multiple-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) model of chronic dermal inflammation (Eur. J. Pharmacol. 1997;334:103–5).

Although triterpenoids are not as prevalent in as many of the highly touted herbal sources as polyphenols, this group of compounds is gaining increased attention for its anti-inflammatory and anti-tumor-promoting activity. In one trial, investigators studying the triterpenoids oleanolic acid and ursolic acid found that the former induced the differentiation of keratinocytes through peroxisome proliferator-activated receptor (PPAR)-α activation. In addition, topical application of oleanolic acid improved the recovery of epidermal permeability barrier function and increased ceramides in epidermis (Exp. Dermatol. 2006;15:66–73).

The preponderance of data on triterpenoids, though, points to the anti-tumor-promoting capacity of this copious botanical class of compounds.

Anti-Tumor-Promoting Actions

In a study designed to identify potential anti-tumor promoters, investigators screened 21 cucurbitane triterpenoids using an in vitro assay system, and found that several of the compounds significantly inhibited Epstein-Barr virus (EBV) activation induced by the tumor promoter TPA.

These compounds were scandenoside R6, 23,24-dihydrocucurbitacin F, 25-acetyl-23,24-dihydrocucurbitacin F, 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, and cucurbitacin F. Two triterpenoids, 23,24-dihydrocucurbitacin F and 2-O-beta-D-glucopyranosyl-23,24-dihydrocucurbitacin F, also displayed significant activity against skin tumor promotion in an in vivo two-stage murine carcinogenesis model (Biol. Pharm. Bull. 1994;17:668–71).

A later in vitro study conducted by the same lab to identify anti-tumor promoters considered 23 triterpenoid hydrocarbons isolated from ferns. Significant inhibitory activity against EBV induced by TPA was exhibited by hop-17(21)-ene, neohop-13(18)-ene, neohop-12-ene, taraxerane, multiflor-9(11)-ene, multiflor-8-ene, glutin-5(10)-ene, and taraxastane. In a two-stage in vivo murine carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and TPA for promotion, hop-17(21)-ene and neohop-13(18)-ene displayed significant anti-tumor promoting effects on mouse skin (Biol. Pharm. Bull. 1996;19:962–5).

Three years later, some of the same investigators, studying triterpenoids derived from Taraxacum japonicum (Compositae) roots, found that taraxasterol and taraxerol significantly inhibited the effects of TPA-induced Epstein-Barr virus early antigen (EBV-EA) induction, which is a preliminary in vitro screening approach to identifying anti-tumor-promoting agents. These compounds also exhibited potent anti-tumor-promoting activity in the two-stage murine skin carcinogenesis model initiated by DMBA and promoted by TPA (Biol. Pharm. Bull. 1999;22:606–10).

In a study from Osaka (Japan) University of Pharmaceutical Sciences, seven serratane-type triterpenoids isolated from different Picea species all exhibited potent inhibitory effects on EBV-EA activation induced by TPA, and did so more strongly than oleanolic acid. In addition, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol displayed significant anti-tumor-promoting activity in the in vivo two-stage murine carcinogenesis model (Cancer Lett. 2001;172:119–26).

The same lab subsequently studied 11 serratane-type triterpenoids isolated from various Picea species and three synthetic analogues for their potential inhibitory effects on EBV-EA activation induced by TPA. That study yielded more corroborative findings, as several of the compounds showed potent inhibitory activity, again more strongly than the oleanolic control, including 21-episerratenediol, serratenediol, diepiserratenediol, 3-beta-hydroxyserrat-14-en-21-one, and 3-alpha-methoxy-21-beta-hydroxyserrat-14-en-16-one. Furthermore, no cytotoxicity was associated with these compounds.

Of these triterpenoids, 21-episerratenediol was found to demonstrate significant inhibitory effects on skin tumor promotion in the in vivo two-stage mouse skin carcinogenesis model using DMBA for initiation and TPA for promotion. The investigators suggested that the triterpenoid 21-episerratenediol has potential as an effective cancer chemopreventive agent (Cancer Lett. 2003;196:121–6).

In a separate experiment conducted by this lab, two new serratane-type triterpenoids, 3beta-methoxyserrat-13-en-21-beta-ol and 13-beta,14beta-epoxy-3beta-methoxyserratan-21beta-ol, also isolated from Picea plants, exhibited strong anti-tumor-promoting effects on mouse skin carcinogenesis (Planta Med. 2003;69:1041–7).

This lab also showed that, in a test of the lupane-type triterpenoids isolated from the stem bark of Glochidion zeylanicum as well as synthetic analogues, glochidiol and lup-20(29)-ene-1beta,3beta-diol were the strongest inhibitors of EBV-EA activation induced by TPA. Glochidiol also exhibited the greatest inhibitory effect on skin tumor promotion (Planta Med. 2004;70:1234–6).

Other Anticarcinogenic Actions

In 2005, investigators at the University of North Carolina, Chapel Hill, published a report on cimigenol, an acid- and base-stable triterpenoid found in species such as Cimicifuga racemosa, C. dahurica, and C. japonica. These researchers had previously shown that cimigenol and some of its derivatives had strong inhibitory effects on mouse skin tumor promotion induced by TPA in a two-stage carcinogenesis test. Continuing that previous work, the investigators repeated screens of cimigenol and also tested 15 related compounds as potential anti-tumor promoters by using the in vitro, short-term TPA-induced EBV-EA activation assay (Bioorg. Med. Chem. 2005;13:1403–8).

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