Inhibition of ornithine decarboxylase

Eflornithine (difluoromethylornithine, DFMO) inhibits the ornithine decarboxylase of the polyamine pathway, in both the trypanosome and the mammalian cell, by acting as an irreversible competitor of the natural substrate ornithine. Inhibition of ornithine decarboxylase results in depletion of the polyamines, putrescine, spermidine and spermine, which are essential for cell proliferation. Eflornithine selectively harms the parasite and not the mammalian cells, despite acting as an ornithine decarboxylase inhibitor in both cell types. This selectivity is explained by the lower rate of ornithine decarboxylase production in the parasite, as compared to mammalian cells. Due to the high turnover rate, mammalian cells are capable of quickly replenishing inhibited ornithine decarboxylase by newly... 

Tilson HA, Emerich D, Bondy SC. 1986a. Inhibition of ornithine decarboxylase alters neurological responsiveness to a tremorigen. Brain Res 379(1) 147-150... 

Metabolism of polyamines has a direct action on cell proliferation. Thus, it is a therapeutic target for the design of antitumor agents. However, inhibition of ornithine decarboxylase (ODC) by specific inhibitors does not completely cancel the activity. This is due to the existence of other biosynthetic pathways (i.e., SAM-DC). These pathways are themselves regulated by polyamines. 

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. 

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... 

Ulrich S, Huwiler A, Loitsch S, Schmidt H, Stein JM. 2007. De novo ceramide biosynthesis is associated with resveratrol-induced inhibition of ornithine decarboxylase activity. Biochem Pharmacol 74 281-289. 

As already mentioned (see section 3.1) lipid peroxides can also break down non-enzymically to yield a variety of carbonyls, such as the hydroxyalkenals [54]. These aldehydes, and in particular 4-hydroxynonenal (HNE), can react with thiol and amino groups of nearby proteins, affecting several enzymic activities [55], These effects however appear to occur at HNE concentrations greater than 10 [lM. At low non-toxic concentrations other effects have been observed which have considerable relevance to cell proliferation. These include the stimulation of adenyl-cyclase and phospholipase C activity in liver membranes [56,57] and an inhibition of ornithine-decarboxylase activity [58] and the expression of globin genes and the protooncogene c-myc in K562 murine leukaemia cells [59]. 

Inhibition of nuclear factor kappa B (NF-kB) activity Inhibition of NO production by NOR-1 Inhibition of ornithine decarboxylase (ODC)... 

The effect of curcumin on apoptosis in multidmg-resistant cell lines has been reported. Piwocka et al. ° demonstrated that curcumin induced cell death in multidrag-resistant CEM(P-gp4) and LoVo(P-gp4) cells in a caspase-3-independent maimer. Mehta et al. also examined the antiproliferative effects of curcumin against multidrag-resistant (MDR) lines, which were found to be highly sensitive to curcumin. The growth-inhibitory effect of curcumin was time- and dose-dependent and was correlated with its inhibition of ornithine decarboxylase activity. Curcumin preferentially arrested cells in the G2/S phase of the cell cycle. 

Poso, A. R., and Poso, H., 1980, Inhibition of ornithine decarboxylase in regenerating rat liver by acute ethanol treatment, Biochim. Biophys. Acta 606 338. 

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