Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

Tang, Xiuwei; Kim, Arianna L.; Feith, David J.; Pegg, Anthony E.; Russo, Justin; Zhang, Hong; Aszterbaum, Michelle; Kopelovich, Levy; Epstein, Ervin; Bickers, David R.; Athar, Mohammad

doi:10.1172/jci200420732

Cited by 64 publications

(51 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experimental data indicated that tumor development and progression to a malignant phenotype were dependent on the elevated levels of ODC and polyamines (45). Hence, assessment of mucosal ODC activity may be of value as a marker for the potential risk of malignancy in the human large bowel and upper gastrointestinal tract (46), and as a molecular target for the chemoprevention of some carcinomas (47).…”

Section: Discussionmentioning

confidence: 99%

l-Arginine Reduces Cell Proliferation and Ornithine Decarboxylase Activity in Patients with Colorectal Adenoma and Adenocarcinoma

Wang

Gao

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Evidence suggests that the majority of colorectal carcinomas arise from adenomas, and L-arginine suppresses colorectal tumorigenesis. We suppose that L-arginine may inhibit the process of carcinogenesis from colorectal adenoma to adenocarcinoma. The aim of this study was to investigate the effects of L-arginine on the formation and development of colorectal tumors. Experimental Design: We selected 60 patients with colorectal cancer and 60 patients with colorectal adenoma (CRA) and divided them into four groups of 30 patients each.We gave 30 g (120 mL) of L-arginine everyday for 3 days to the test groups, whereas L-arginine was substituted by 5% glucose in the control groups. The expression of the proliferating cell nuclear antigen, survivin, and nitric oxide synthase was examined immunohistochemically, and ornithine decarboxylase (ODC) activity was examined spectrophotometrically. Serum nitric oxide (NO) was detected by the Griess assay. Results: In patients with CRA, the proliferating cell nuclear antigen and survivin labeling indexes and ODC activity of the tumor and paratumor mucosa in the L-arginine^treated group after L-arginine treatment were significantly lower as compared with the corresponding pretreatment values (P < 0.01). Moreover, inducible nitric oxide synthase expression in the tumor markedly increased after L-arginine treatment (P < 0.05). Serum NO levels in the patients with colorectal cancer were markedly higher than those in the patients with CRA, and L-arginine treatment was responsible for this increase (P < 0.05). Conclusions:Our results show that L-arginine can restrain crypt cell hyperproliferation and the expression of survivin, an inhibitor of apoptosis protein. This suggests that L-arginine can block the formation and development of colorectal tumors, and this effect might be related to the increased serum NO concentration and decreased ODC activity.Colorectal carcinoma (CRC) is one of the most common cancers in the world, and colorectal adenoma (CRA) is known to be a precursor of both sporadic and hereditary CRC. Recent studies have shown that the frequency of adenomas in a population with an increased risk of CRC is higher as compared with that in the general population; moreover, patients with the so-called hereditary nonpolyposis syndrome also had an earlier onset of adenomas and faster progression to cancer (1). It is widely accepted that environmental factors, particularly dietary factors, are involved in the etiology of CRC. A high intake of fat, red meat, and energy have not only been associated with an increased risk of CRC (2 -5), but have also influenced the 5-year survival in the patients who underwent surgical treatment for CRC (6). Therefore, developing strategies to decrease the incidence of CRC and improve its prognosis by changing the diet or certain dietary components have currently become a hot topic of study. The focus on L-arginine supplements has been increasing in recent years.L-Arginine, a semiessential amino acid, is required for the synthesis...

show abstract

Section: Discussionmentioning

confidence: 99%

l-Arginine Reduces Cell Proliferation and Ornithine Decarboxylase Activity in Patients with Colorectal Adenoma and Adenocarcinoma

Wang

Gao

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Clinical trials with DFMO have shown no or only limited overall survival benefits in cancer patients, which most probably relates to the cytostatic rather than cytotoxic effect of DFMO in vivo (11). The drug was relatively well tolerated, and more recent studies implicate an interesting role of DFMO as a chemopreventive drug for use in, for example, colorectal cancer, squamous cell carcinomas, and prostate cancer (11,29). The combined effect of DFMO and antiangiogenic strategies has, to our knowledge, never been tested.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase

Svensson¹,

Welch²,

Kucharzewska³

et al. 2008

Cancer Research

View full text Add to dashboard Cite

Hypoxia is a hallmark of solid tumors, which may offer opportunities for targeted therapies of cancer; however, the mechanisms that link hypoxia to malignant transformation and tumor progression are not fully understood. Here, we show that up-regulation of the polyamine system promotes cancer cell survival during hypoxic stress. Hypoxia was found to induce polyamine transport and the key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), in a variety of cancer cell lines. Increased ODC protein expression was shown in hypoxic, GLUT-1-expressing regions of tumor spheroids and experimental tumors, as well as in clinical tumor specimens. Hypoxic induction of the polyamine system was dependent on antizyme inhibitor (i.e., a key positive regulator of ODC and polyamine transport), as shown by RNA interference experiments. Interestingly, depletion of the polyamines during hypoxia resulted in increased apoptosis, which indicates an essential role of the polyamines in cancer cell adaptation to hypoxic stress. These results were supported by experiments in an in vivo glioma tumor model, showing significantly enhanced antitumor effects of the antiangiogenic, humanized anti-vascular endothelial growth factor (VEGF) antibody bevacizumab when used in combination with the well-established, irreversible inhibitor of ODC, A-difluoromethylornithine. Our results provide important insights into the hypoxic stress response in malignant cells and implicate combined targeting of VEGF and ODC as an alternative strategy to treat cancer disease. [Cancer Res 2008;68(22):9291-301]

show abstract

“…These sustained high levels of putrescine lead to alopecia, the development of follicular dermal cysts, increased nail growth, and skin wrinkling. With regard to tumor development, the targeted expression of ODC to the skin also increases the susceptibility of these mice to skin tumor formation following a variety of initiating events including carcinogens (O'Brien et al, 1997;Chen et al, 2000), UV irradiation (Ahmad et al, 2001), and oncogenes (Smith et al, 1998;Tang et al, 2004;Lan et al, 2005). The treatment of newborn or adult K6/ODC transgenic mice with a single topical application of the carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA) yields papilloma formation six to eight weeks later without the use of tumor promoting agents (O'Brien et al, 1997;Peralta Soler et al, 1998).…”

Section: Odc and Nonmelanoma Skin Tumorigenesismentioning

confidence: 99%

“…Bi-transgenic mice expressing both skin-targeted ODC and the v-Ha-ras oncogene develop spontaneous keratoacanthomas and squamous cell carcinomas, whereas no tumors develop in the mono-transgenic mice (Smith et al, 1998;Lan et al, 2005). On the other hand, basal cell carcinomas develop in mice that are both heterozygous null for the patched tumor suppressor gene and overexpressing ODC in follicular cells (Tang et al, 2004).…”

Section: Odc and Nonmelanoma Skin Tumorigenesismentioning

confidence: 99%

“…Furthermore, overexpression of AZ in the skin of transgenic mice leads to decreased ODC activity following tumor promoter treatment and also suppresses tumor growth in the classic DMBA/TPA skin tumorigenesis model (Feith et al, 2001) and in the UV carcinogenesis model using the Ptch +/-heterozygous mouse model (Tang et al, 2004). Both DFMO and AZ inhibition of skin tumor development primarily inhibit the accumulation of putrescine, whose levels correlate very closely with tumor development in the skin (Peralta Soler et al, 1998).…”

Section: Odc and Nonmelanoma Skin Tumorigenesismentioning

confidence: 99%

See 1 more Smart Citation

Polyamines and nonmelanoma skin cancer

Gilmour

2007

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Elevated levels of polyamines have long been associated with skin tumorigenesis. Tightly regulated metabolism of polyamines is critical for cell survival and normal skin homeostasis, and these controls are dysregulated in skin tumorigenesis. A key enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) is upregulated in skin tumors compared to normal skin. Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. The formation of skin tumors in these transgenic mice is dependent upon polyamine biosynthesis, especially putrescine, since treatment with inhibitors of ODC activity blocks the formation of skin tumors and causes the rapid regression of existing tumors. Although the mechanism by which polyamines promote skin tumorigenesis are not well understood, elevated levels of polyamines have been shown to stimulate epidermal proliferation, alter keratinocyte differentiation status, increase neovascularization, and increase synthesis of extracellular matrix proteins in a manner similar to that seen in wound healing. It is becoming increasingly apparent that elevated polyamine levels activate not only epidermal cells but also underlying stromal cells in the skin to promote the development and progression of skin tumors. The inhibition of polyamine biosynthesis has potential to be an effective chemoprevention strategy for nonmelanoma skin cancer.

show abstract

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

Cited by 64 publications

References 53 publications

l-Arginine Reduces Cell Proliferation and Ornithine Decarboxylase Activity in Patients with Colorectal Adenoma and Adenocarcinoma

l-Arginine Reduces Cell Proliferation and Ornithine Decarboxylase Activity in Patients with Colorectal Adenoma and Adenocarcinoma

Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase

Polyamines and nonmelanoma skin cancer

Contact Info

Product

Resources

About