Inhibition of murine embryonic development by α-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase

Fozard, John R.; Part, Marie-Louise; Prakash, Nellikunja J.; Grove, Jeffrey

doi:10.1016/0014-2999(80)90342-8

Cited by 80 publications

(28 citation statements)

References 18 publications

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“…DFMO exposure did not prevent estrus-diestrus as measured by the vaginal smear technique (Cooper et al, 1993) and did not alter ovarian histology. It is likely that the inhibitory effect of DFMO on pregnancy is secondary to effects on the uterus consistent with previous reports from the rat (Fozard et al, 1980;Reddy and Rukmini, 1981).…”

supporting

confidence: 89%

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Ren

Tilli

et al. 2003

Oncogene

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Mechanisms underlying the chemopreventive effect of difluoromethylornithine (DFMO) on the development of mammary cancer were investigated utilizing the whey acidic protein promoter-T antigen transgenic mouse model of breast cancer progression. Mice were exposed to four different doses of DFMO in the diet (3.5, 4.9, 7.0 and 10 g/kg diet). Tumor latency was increased in a dosedependent manner. DFMO at the highest dose significantly delayed tumor onset (131 days as compared to 109 days in control unexposed mice, P ¼ 0.018). Analyses of preneoplastic mammary tissue collected 1 month after DFMO treatment demonstrated that DFMO (10 g/kg diet) significantly increased the ratio of apoptotic to proliferative indices (P ¼ 0.013) and significantly reduced the percentage of cells demonstrating nuclear localized cyclin D1 (P ¼ 0.013). Nuclear localizations of p27, p21 and Stat5a were not affected. Inhibitory effects of DFMO on cell growth and survival were lost as the cells progressed to cancer. In conclusion, the chemopreventive effects of DFMO on mammary cancer progression were mediated by changes in both apoptosis and cell proliferation in preneoplastic cells. Alterations in cyclin D1 activity in preneoplastic cells could represent an early biomarker of chemopreventive action and are consistent with a mechanistic role for cyclin D1 in progression of mammary cancer.

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supporting

confidence: 89%

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Ren

Tilli

et al. 2003

Oncogene

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“…Inhibition of NOS might increase the production of polyamines. Polyamines are essential in embryo implantation (Fozard et al 1980b). ODC was strongly expressed in implantation sites.…”

Section: Discussionmentioning

confidence: 98%

Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy

Zeng¹,

Mao²,

Huang³

et al. 2013

Reproduction

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Our previous study has demonstrated that dietary arginine supplementation during early pregnancy enhanced embryo implantation in rats. However, the mechanism was not clear. The objective of this study was to determine the mechanism that arginine enhanced embryo implantation during early pregnancy. Rats were fed the basal diets supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) once pregnancy. On d4 of pregnancy, rats were given intrauterine injection of L-NG-nitro arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), a-difluoromethylornithine (DFMO, polyamine synthesis inhibitor), wortmannin (PI3K inhibitor), or rapamycin (mTOR inhibitor). On d7 of pregnancy, rats were killed. Intrauterine injection of L-NAME decreased the implantation sites, while dietary arginine supplementation increased the implantation sites. Intrauterine injection of DFMO decreased the pregnancy rate, which was reversed by dietary arginine supplementation. Intrauterine injection of rapamycin or wortmannin inhibited embryo implantation. However, dietary arginine supplementation did not reverse this inhibition. Western blot analysis revealed that the expression of uterine p-PKB and p-S6K1 was greater in rats fed the arginine-supplemented diet in the presence of L-NAME treatment compared with rats fed the control diet. In the presence of DFMO treatment, the expression of uterine iNOS and eNOS was significantly enhanced in the arginine group compared with the control group. Similarly, intrauterine injection of wortmannin or rapamycin decreased the expression of uterine iNOS and eNOS, which was enhanced by dietary arginine supplementation. These data indicated that dietary arginine supplementation during early pregnancy could enhance embryo implantation through stimulation of PI3K/PKB/mTOR/NO signaling pathway.

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“…Furthermore, chicken embryos injected with DFMO have marked reductions in their polyamine levels and fail to develop past gastrulation (22). Similarly, scheduled administration of DFMO during pregnancy in mice induces resorption of embryos when introduced at gestational days 7 and 8 (17). However, these inhibitors may have other targets, and these experiments fail to discriminate whether arrest in embryonic development is due to a lack of maternal ODC or zygotic ODC.…”

Section: Discussionmentioning

confidence: 99%

The Ornithine Decarboxylase Gene Is Essential for Cell Survival during Early Murine Development

Pendeville

Carpino²,

Marine

et al. 2001

Molecular and Cellular Biology

232

176

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Overexpression and inhibitor studies have suggested that the c-Myc target gene for ornithine decarboxylase (ODC), the enzyme which converts ornithine to putrescine, plays an important role in diverse biological processes, including cell growth, differentiation, transformation, and apoptosis. To explore the physiological function of ODC in mammalian development, we generated mice harboring a disrupted ODC gene. ODC-heterozygous mice were viable, normal, and fertile. Although zygotic ODC is expressed throughout the embryo prior to implantation, loss of ODC did not block normal development to the blastocyst stage. Embryonic day E3.5 ODCdeficient embryos were capable of uterine implantation and induced maternal decidualization yet failed to develop substantially thereafter. Surprisingly, analysis of ODC-deficient blastocysts suggests that loss of ODC does not affect cell growth per se but rather is required for survival of the pluripotent cells of the inner cell mass. Therefore, ODC plays an essential role in murine development, and proper homeostasis of polyamine pools appears to be required for cell survival prior to gastrulation.Overexpression of the c-Myc, N-Myc, or L-Myc members of the Myc oncogene family is a common event in human tumors. This selection likely reflects Myc's ability to provide continuous proliferative and angiogenic signals under growth-limiting conditions, such as those that occur in the tumor microenvironment (38). However, Myc's propensity to induce continuous proliferation also blocks terminal differentiation (11) and triggers the apoptotic program (2). c-Myc is a basic helix-loophelix leucine zipper protein that exhibits sequence-specific DNA binding to CACGTG or CACATG elements when dimerized with its obligate basic helix-loop-helix leucine zipper partner Max (8). Despite Myc's well-defined function as a transcriptional transactivator, the numbers of its ascribed targets that have been proven to be direct are relatively few, but they do include ornithine decarboxylase (ODC) (6), ␣-prothymosin (15), eIF-4E (44), carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase (cad) (28), a DEAD box-related gene (MrDb) (20), the ubiquitin E2 ligase Cul1 (32), and ECA39 (7). A compelling example of a target gene that contributes to c-Myc's biological effects is ODC (34, 35), which is activated by growth factors and by c-Myc through two conserved CACGTG sites present in the first intron of vertebrate ODC genes (6). ODC is the key regulator of the polyamine biosynthetic pathway and decarboxylates L-ornithine to form putrescine (50). ODC expression is highly regulated by changes in its transcription, translation, and RNA and protein half-life (40). Furthermore, ODC enzyme activity is tightly controlled and shows biphasic induction during late G 1 and at G 2 /M (5). Inhibition of ODC by difluoromethylornithine (DFMO) compromises cell growth and transformation (3) and induces cell cycle arrest in G 1 (35,43). ODC inhibition results in marked reductions in the intracellular levels of th...

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Inhibition of murine embryonic development by α-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase

Cited by 80 publications

References 18 publications

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy

The Ornithine Decarboxylase Gene Is Essential for Cell Survival during Early Murine Development

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