Ornithine decarboxylase , effects

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

In animal studies, mirex (a nonmutagenic hepatocarcinogen) promoted mouse skin squamous carcinomas and papillomas after initiation with 7,12-dimethyl-benz[a]anthracene (DMBA) for 1 week. Mirex, also, potentiated the promotional potency of the phorbol ester tumor promoter, 12-0 -tetradecanoylphorbol-13-acetate (TPA). There was a 90% incidence (activation) of the c-Ha-ras tumor gene in these co-promoted tumors. When both mirex and TPA gave a similar tumor yield, only the TPA response was associated with biochemical markers of enhanced cell proliferation, induction of epidermal ornithine decarboxylase activity and increased DNA synthesis, and hyperplasia. Thus, there is evidence for a dual effect of mirex during co-promotion first, as an independent tumor promoter with a mechanism different than that of phorbol esters and second, as a compound that also potentiates skin tumor promotion by TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). 

Pretreatment of rats with difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, prior to exposure to a tremorigenic dose of chlordecone, also resulted in inhibition of the tremor (Tilson et al. 1986b). DFMO was more effective if given 5 hours prior to the chlordecone than if given 24 hours prior to exposure. The DFMO was ineffective if given 19 hours after chlordecone exposure. These results suggest an interaction of the polyamine synthetic pathway with tremors produced by chlordecone. The mechanism of the interaction is unclear but may involve effects of polyamines on intracellular calcium homeostasis. Persons being treated with DFMO for cancer or protozoal infections would be likely to have reduced tremor severity after exposure to chlordecone. 

Yatin SM, Yatin M, Aulick T, Ain KB, Butterfield DA. (1999). Alzheimer s amyloid beta-peptide associated free radicals increase rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity protective effect of vitamin E. Neurosci Lett. 263(1) 17-20. 

Ornithine decarboxylase activity. Fixed oil (4.5%), Clupeidae brevortia tyrannus (4%), and Zea mays (1.5%) fixed oil (7.5%), Clupeidae brevortia tyrannus (1%), and Zea mays (1.5%) fixed oil (8.5%) and Zea mays (1.5%), administered orally to mice for 1 year, were active vs benzoyl peroxide-induced ornithine decarboxylase activity Oil, administered to 30 ultraviolet (UV)-irradiated Senear and SKH-1 mice at doses of 1/14% (A diet), 7.9/7.1% (B diet), and 15/0% (C diet) corn oil/coco-nut oil for 6 weeks, produced no increase in enzyme activity. The level of ornithine decarboxylase activity in the UV-irradiated mice fed diet A was significantly higher than in mice fed the B or C diet. In the SKH-1 mice, ornithine decarboxylase activity was increased by 3 weeks and was significantly higher in mice fed diet C than in mice fed diet A. There was no significant effect of dietary fat on UV-induced skin tumor incidence ". 

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... 

Bhide. Effects of tobacco-specific nitrosamines and snuff extract on cell proliferation and activities of ornithine decarboxylase and aryl hydrocarbon hydroxylase in mouse tongue primary epithelial cell cultures. J Cancer Res Clin Oncol 1989 115(6) 558-563. 

ZO024 Park, K. K., K. S. Chum, ]. M. Lee, S. S. Lee, and Y. ]. Surh. Inhibitory effects of [6]-gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Lett 1998 129(2) 139-144. 

Mechanism of Action A topical antiprotozoal that inhibits ornithine decarboxylase cell division and synthetic function in the skin. Therapeutic Effect Reduces rate of hair growth. 

After 7 days, lungs of high-dose group had elevated putrescine, spermidine, and ornithine decarboxylase activity, reflecting changes in polyamine metabolism no measurable effects in low-dose group (Dunbar et al. 1988b)... 

Effect of CLA on Protein Kinase C (PKC) Activity. 12-0-tetradecanoylphorbol-13-acetate (TPA) administered by gavage induced the activity of ornithine decarboxylase (ODC) in a similar manner to that observed in mouse skin (28). The peak activity was about 5-times control and occurred 6 hrs after TPA intubation. Treating mice with CLA (100 mg p. o., twice per week) for 1, 2 or 4 weeks progressively reduced the TPA... 

RLV/Fischer rat assay without the addition of an exogenous metabolic activation system. In a single study, mouse JB6 epidermal cells were transformed by di(2-ethyl-hexyl) phthalate without activation and in one of two studies a weak response was reported in the CSHIOT A cell transformation assay with di(2-ethylhexyl) phthalate in either the absence or presence of exogenous metabolic activation. BALB/c-3T3 cells were not transformed by di(2-ethylhexyl) phthalate with or without metabolic activation. Di(2-ethylhexyl) phthalate inhibited gap-junctional intercellular communication in Chinese hamster V79 cells in six of seven studies, but not in one study of liver cells of cynomolgus monkeys in vivo. Di(2-ethylhexyl) phthalate treatment of Syrian hamster embryo cells in a two-stage exposure with 12-O-tetradecanoylphorbol 13-acetate resulted in superinduction of ornithine decarboxylase, an early event in morphological transformation no effect was seen after a one-stage treatment with di(2-ethylhexyl) phthalate alone. 

Eflornithine (Vaniqa) is an irreversible inhibitor of ornithine decarboxylase, which catalyzes the rate-limiting step in the biosynthesis of polyamines. Polyamines are required for cell division and differentiation, and inhibition of ornithine decarboxylase affects the rate of hair growth. Topical eflornithine has been shown to be effective in reducing facial hair growth in approximately 30% of women when applied twice daily for 6 months of therapy. Hair growth was observed to return to pretreatment levels 8 weeks after discontinuation. Local adverse effects include stinging, burning, and folliculitis. 

In mammalian cells, ornithine decarboxylase undergoes rapid turnover—that is, a constant round of enzyme degradation and synthesis. In some trypanosomes, however, the enzyme—for reasons not well understood—is stable, not readily replaced by newly synthesized enzyme. An inhibitor of ornithine decarboxylase that binds permanently to the enzyme would thus have little effect on human cells, which could rapidly replace inactivated enzyme, but would adversely affect the parasite. 

The mechanisms by which antitumor-promoters suppress the tumor promotion are not known, but may be due to the following effects (i) inhibition of polyamine metabolism (ii) inhibition of arachidonic acid metabolism (iii) protease inhibition (iv) induction of differentiation (v) inhibition of oncogene expression (vi) inhibition of PKC and (vii) inhibition of oxidative DNA damage [3,6,91]. The polyamine content of cells is correlated to their proliferative, and often, their neoplastic capabilities. A key enzyme in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC), catalyzes the convertion of ornithine to putrescine. Phorbol ester promoters such as TPA cause increased ODC activity and accumulation of polyamines in affected tissues. Diacylglycerol activated PKC, and the potent tumor promoter, TPA, binds to, and activates PKC, in competition with diacylglycerol. PKC stimulation results in phosphorylation of regulatory proteins that affect cell proliferation. Some chemopreventive agents have inhibitory activity towards PKC. Refer to recent review articles for further discussion [3,6,91]. 

Huang et al. [70] have evaluated the effects of chlorogenic acids on tumor promotion in an animal study using CD-I mice. Chlorogenic, caffeic and ferulic acids inhibit the induction of ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate (TPA). TPA-mediated DNA synthesis has been weakly inhibited, but TPA-induced skin tumor promotion has been markedly inhibited by these compounds. 

Resveratrol exerts antitumor effects partly by arresting the growth of various cancer cells in culture [Kundu and Surh, 2004]. The inhibition of ornithine decarboxylase (ODC), a biochemical hallmark of tumor promotion, has been shown to account for the antiproliferative and antitumor effects of resveratrol [Schneider et al., 2000 Ulrich et al., 2007]. Aberrant changes in cell-cycle machinery are considered as the biochemical basis of abnormal proliferation of transformed cells. Major cell-cycle regulatory proteins include various cyclins, cyclin-dependent kinases (Cdk), Cdk inhibitors, and check point kinases (Chkl... 

Ornithine decarboxylase catalyzes the transformation of ornithine to the polycationic bases, putresine, spermine, and spermidine. These compounds exert regulatory effects on cell growth. It has been shown that quercetin (10 to 30 pmol/mouse) markedly suppressed the stimulatory effect of the transporters associated with antigen processing (TPA) on ornithine decarboxylase (ODC) activity and on skin tumor formation in mice initiated with dimethylbenzanthracene. Such inhibition may be related to the activation of the catalytic site, which is under nonconventional regulation by small molecules. Also, the synthetic flavonoid flavone acetic acid was shown to inhibit the activity of ODC in stimulated human peripheral blood lymphocytes and human colonic lamina propria lymphocytes. 

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