TPA-induced EBV activation

In 2004, Fumkawa and co-workers reported the isolation of glybomine B (60) and glybomine C (61), along with glybomine A (42) (see Scheme 2.9), from the stem of G. arborea (68). This group of carbazole alkaloids showed antitumor-promoting activity against (12-0-tetradecanoylphorbol-13-acetate) TPA-induced EBV-EA activation. 

Table 6. Inhibitory Effects of Some Terpenoids on TPA-induced EBV-EA Activation"...

ABSTRACT This review covers various bioactive quassinoids in Simaroubaceous plants, which show cytotoxic antitumor, anti-tumor-promoter (= inhibitor against TPA-induced EBV-EA activation), anti-HIV, anti-tuberculosis, insect antifeedant, and other biological activities. Stability of quassinoids, the preparation of their derivatives, and their biological activities are also discussed. 

In a previous paper [1], we reviewed the isolation of quassinoids, alkaloids, and fatty acids from Simaroubaceous plants during the period 1972-1988 and discussed their biological activities, such as antitumor, antimalarial, and anti-inflammatory agents as well as insect antifeedants, amoebicides, and herbicides. This review will add new quassinoids isolated from Simaroubaceous plants from 1988 onwards and their biological activities, for example, antitumor, anti-tumor-promotor (= inhibitor against TPA-induced EBV-EA activation), anti-HIV, anti-tuberculosis, and insect antifeedant activities. Furthermore, the stability of quassinoids, lower activities of degradation products, and the synthesis of fluorinated quassinoids are also described. 

Table 3. Inhibitory Effects of Dihydroagarofuran Sesquiterpenes on TPA-Induced EBV-EA Activation...

Epstein-Barr virus early antigen induction. Methanol extract of the dried leaf, in cell culture at a concentration of 1 pg/mL, was inactive. The assay was designed for tumor-promoting activity . Two diastere-oisomers of 2,7,1 l-cembratriene-4,6-diol (a- and 3-CBT) from the neutral fractions of cigarette smoke condensate, in Raji cells, produced potent inhibitory effects on the induction of Epstein-Barr virus (EBV)-EA by 12-0-tetradecanoylphorbol-13-acetate (TPA). The doses of a- and P-CBT required for 50% inhibition of EBV-EA induction by TPA were 7.7 and 6.7 mg/mL, respectively. Application of a- and P-CBT to mouse skin before treatment with TPA, inhibited TPA-induced ornithine decarboxylase activity in a dose-dependent manner. Application of 16.5 pM/mouse of a- and p-CBT resulted... 

Soyasapogenol B, soyasaponins I and II and wistariasaponins from Wistaria brachybotrys (wistariasaponin C corresponds to astragaloside VIII) decreased (20-30%) the Epstein-Barr Virus (EBV) activation induced by the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate) in Raji cells at a concentration of lxlO2 mol ratio [151]. Soyasaponin I from the same plant exhibited remarkable inhibitory effects on mouse skin tumor promotion on the basis of the two-stage DMBA-TPA carcinogenesis test in vivo. Soyasaponin I reduced the number of papillomas per mouse at about 40% even at 20 weeks [152]. 

Several terpenoids have been evaluated for their inhibitory effects on EBV-EA activation induced by TPA. Table 6 shows the inhibitory effects of monoterpenoids [70,71], sesquiterpenoids [20,119-123], diterpenoids [21,123-131], and meroterpenoids [117] against TPA (32 pmol, 20 ng)-induced EBV-EA activation in Raji cells. The inhibitory effects were compared with that of [3-carotene, a vitamin A precursor that has been studied intensively in cancer chemoprevention using animal models [2,4]. All of the terpenoids tested caused higher viability (60-80%) of Raji cells even at mol ratio of compound to TPA = 1000 1 indicating their very low cytotoxicity at that high concentration (refer to Table 6). 

In recent years, the anti-tumor-promoting activities of several natural products [102] have been investigated for inhibition of 12-0-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation [103]. Compounds isolated from T. wilfordii var. regelii were assayed by Takaishi and coworkers [27] on... 

In a similar screening, Konoshima et al. [72] studied the inhibitory effects of twenty-four 29-nor-cucurbitacin glucosides isolated from the roots of Cayaponia tayuya and found that five of them, cayaponosides B, B3, D, D3b, and C2, exhibited significant inhibitory effects on EBV activation induced by the tumor promoter TPA. Moreover, two of the cucurbitacins shown to be active in vitro, cayaponosides B and C2, Fig. (14), inhibited mouse skin tumor promotion in a two-stage in vivo carcinogenesis test. 

Two triterpene carboxylic acids, ursolic acid (iM) and oleanolic acid (171), Fig. (43) have been reported as inhibitors of 12-0-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus (EBV) activation in Raji cells. Both acids significantly inhibited the activation at a 1000-fold molar ratio to TPA. The dose responses of the acids were very similar to those of the antitumor promoters, retinoic acid and glycyrrhetinic acid. The results suggested that ursolic and oleanolic acids may be valuable antitumor promoters [223]. 

EBV Inhibition of Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA [22-27]... 

Glycyrrhetic acid (147) and retinoic acid are known in vivo antitumor-promoters which inhibit EBV-EA induction by tumor promoters [77]. Oleanolic acid (142) and ursolic acid (210) significantly inhibit the activation induced by TPA and teleocidin B (3) as do 147 and retinoic acid... 

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