Esophageal Cancer Prevention in Zinc-Deficient Rats: Rapid Induction of Apoptosis by Replenishing Zinc

Fong, Louise Y.Y.; Nguyen, Vu T.; Farber, John L.

doi:10.1093/jnci/93.20.1525

Cited by 74 publications

(95 citation statements)

References 29 publications

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“…Our previous work showed that in ZD rats, zinc replenishment prevents NMBA-induced esophageal carcinogenesis. 22 The present data document the similar ability of zinc replenishment to inhibit lingual carcinogenesis in these animals. The lack of efficacy of celecoxib in curbing lingual cancer progression indicates its inability to block other cancer pathways that may be stimulated under nutritional ZD conditions.…”

Section: Discussionsupporting

confidence: 78%

“…Custom-formulated ZD and ZS diets (Harlan Teklad, Madison, WI) were identical except for the amount of zinc, which was 1.5 and 3 ppm for ZD diets for mice and rats and 70 ppm for ZS diet. 16,22 Celecoxib at 100 and 500 ppm was mixed with rat diets. To ensure the animals were fed the assigned food, the diets were shape and color-coded.…”

Section: Chemicals and Dietsmentioning

confidence: 99%

“…13 Zinc replenishment (ZR) rapidly reverses cell proliferation, stimulates apoptosis, corrects abnormal gene expression and inhibits esophageal tumorigenesis. 13,22 Additionally, p53-deficient mice or cyclin D1 overexpressing transgenic mice on a zinc-deficient diet showed rapid development and progression of esophageal/forestomach tumors by NMBA, 16,23 as well as lingual/esophageal tumors by NQO. 24 Since UADT cancer patients are often zinc-deficient, our well-characterized ZD rodent cancer models offer opportunities to explore the biologic role of zinc in UADT cancer development and prevention.…”

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confidence: 99%

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Prevention of upper aerodigestive tract cancer in zinc‐deficient rodents: Inefficacy of genetic or pharmacological disruption of COX‐2

Fong¹,

Jiang²,

Riley³

et al. 2007

Intl Journal of Cancer

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Zinc deficiency in humans is associated with an increased risk of upper aerodigestive tract (UADT) cancer. In rodents, zinc deficiency predisposes to carcinogenesis by causing proliferation and alterations in gene expression. We examined whether in zinc-deficient rodents, targeted disruption of the cyclooxygenase (COX)-2 pathway by the COX-2 selective inhibitor celecoxib or by genetic deletion prevent UADT carcinogenesis. Tongue cancer prevention studies were conducted in zinc-deficient rats previously exposed to a tongue carcinogen by celecoxib treatment with or without zinc replenishment, or by zinc replenishment alone. The ability of genetic COX-2 deletion to protect against chemically-induced forestomach tumorigenesis was examined in mice on zinc-deficient versus zinc-sufficient diet. The expression of 3 predictive biomarkers COX-2, nuclear factor (NF)-j B p65 and leukotriene A 4 hydrolase (LTA 4 H) was examined by immunohistochemistry. In zinc-deficient rats, celecoxib without zinc replenishment reduced lingual tumor multiplicity but not progression to malignancy. Celecoxib with zinc replenishment or zinc replenishment alone significantly lowered lingual squamous cell carcinoma incidence, as well as tumor multiplicity. Celecoxib alone reduced overexpression of the 3 biomarkers in tumors slightly, compared with intervention with zinc replenishment. Instead of being protected, zinc-deficient COX-2 null mice developed significantly greater tumor multiplicity and forestomach carcinoma incidence than wild-type controls. Additionally, zinc-deficient COX-22/2 forestomachs displayed strong LTA 4 H immunostaining, indicating activation of an alternative pathway under zinc deficiency when the COX-2 pathway is blocked. Thus, targeting only the COX-2 pathway in zinc-deficient animals did not prevent UADT carcinogenesis. Our data suggest zinc supplementation should be more thoroughly explored in human prevention clinical trials for UADT cancer. ' 2007 Wiley-Liss, Inc.Key words: zinc deficiency; upper aerodigestive tract cancer; chemoprevention; COX-2; COX-2 null mice Upper aerodigestive tract (UADT) cancer, including esophageal and oral cancer, is an important cause of morbidity and mortality worldwide. 1 With a 5-year survival of 10%, esophageal cancers are deadly. The prognosis of oral cancer, the major site being the tongue, is equally dismal, with an increasing incidence worldwide, particularly in young adults. 2 Patients with oral cancer have a high mortality rate, because of field cancerization effects that result in second primary tumors, particularly in the esophagus. 3,4 Thus, new chemopreventive and therapeutic approaches are much needed to prevent and treat these deadly cancers.While chronic alcohol consumption and tobacco use are the major risk factors for UADT cancer, epidemiologic and clinical studies have implicated dietary zinc deficiency (ZD) in the etiology of esophageal squamous cell carcinoma (SCC) and head and neck SCC. [5][6][7][8][9] In 2005, Abnet et al. 10 provided the strongest evidence of an a...

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Section: Discussionsupporting

confidence: 78%

Section: Chemicals and Dietsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Prevention of upper aerodigestive tract cancer in zinc‐deficient rodents: Inefficacy of genetic or pharmacological disruption of COX‐2

Fong¹,

Jiang²,

Riley³

et al. 2007

Intl Journal of Cancer

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“…Replenishing zinc with a zincsufficient diet reduces these effects in zinc-deficient rats. [33][34][35] Ecologic observations several years ago implicated zinc deficiency in the etiology of esophageal squamous cell carcinoma in the Asian oesophageal cancer belt, and this led to the launching of several large-scale chemoprevention trials. 36,37 However, none of these studies provided any persuasive evidence of any beneficial effects of zinc supplementation in populations deemed to be zinc deficient.…”

Section: Discussionmentioning

confidence: 99%

Heme iron, zinc and upper digestive tract cancer: The Iowa Women's Health Study

et al. 2005

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We examined associations among dietary heme iron as a possible pro-oxidant, dietary zinc as a possible antioxidant, and the incidence of upper digestive tract cancer; 34,708 postmenopausal women, aged 55-69 years at baseline who completed a food frequency questionnaire, were followed 16 years. There were 75 upper digestive tract cancer cases (52 gastric cancer and 23 esophageal cancer). When heme iron and zinc were mutually adjusted, in dose-response manners, heme iron intake was positively associated with the risk of upper digestive tract cancer, while zinc intake was inversely associated with risk. After adjusting for age, total energy intake, cigarette smoking and alcohol consumption, relative risks for quintiles of heme iron intake were 1.0, 1.53, 2.15, 3.05 and 2.83 (p for trend 5 0.06) and corresponding relative risks for zinc intake were 1.0, 0.86, 0.42, 0.37 and 0.13 (p for trend < 0.01). Additional adjustment for body mass index, physical activity, hormone replacement therapy, multivitamin intake and intake of saturated fat, vitamin C, vitamin E and folate did not change the results. Higher intake of heme iron is associated with higher risk, while higher intake of zinc is associated with lower, risk of upper digestive tract cancer. ' 2005 Wiley-Liss, Inc.Key words: heme iron; zinc; esophageal cancer; gastric cancer; oxidative stress Although iron is vital for all living organisms, iron is also potentially carcinogenic due to its catalytic effect on the formation of hydroxyl radicals, suppression of the activity of host defense cells and promotion of cancer cell multiplication. 1,2 On the other hand, zinc has antioxidant properties; zinc ions may replace redox active molecules and may induce the synthesis of metallothionein, sulfhydryl-rich proteins that protect against free radicals. 3 At a molecular level, metals such as iron can substitute for zinc and may be responsible for metal-induced DNA damage and carcinogenesis, 4,5 suggesting a close interrelation of the 2 nutrients. Supporting these observations, we recently reported that intake of dietary heme iron, the most bioavailable form of iron, is associated with an increased risk of proximal colon cancer, while intake of dietary zinc is associated with a decreased risk of both proximal and distal colon cancer. 6 Even though various upper digestive tract cancers have been shown to be distinct entities in terms of many risk factors and pathological and/or clinical features, carcinogenesis due to oxidative stress is not a site-specific mechanism. Many known risk factors in carcinogenesis such as infection, inflammation, cigarette smoking, nutrition or alcohol consumption may ultimately be associated with oxidative stress as a unifying underlying mechanism. 7-10 For example, oxidative stress associated with inflammation plays an important role in gastric carcinogenesis as a mediator of carcinogenic compound formation, DNA damage and cell proliferation. 7 Similarly, oxidative stress also has been suggested to be a driving force in the pathogenesis of eso...

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“…Zinc deficiency has been shown to cause esophageal tumors in rats (14) and also in conjunction with a single low dose of a nitrosamine (15,16). Replenishment of zinc in zinc-deficient (ZnDF) rats has been shown to induce apoptosis in esophageal epithelial cells and thereby reduces the development of esophageal cancer (17). Zinc deficiency can also lead to increased oxidative damage to testicular cell DNA (18,19).…”

mentioning

confidence: 99%

Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFκB, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line

Ames

2002

Proc. Natl. Acad. Sci. U.S.A.

366

269

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Approximately 10% of the U.S. population ingests <50% of the current recommended daily allowance for zinc. We investigate the effect of zinc deficiency on DNA damage, expression of DNA-repair enzymes, and downstream signaling events in a cell-culture model. Low zinc inhibited cell growth of rat glioma C6 cells and increased oxidative stress. Low intracellular zinc increased DNA single-strand breaks (comet assay). Zinc-deficient C6 cells also exhibited an increase in the expression of the zinc-containing DNA-repair proteins p53 and apurinic endonuclease (APE). Repletion with zinc restored cell growth and reversed DNA damage. APE is a multifunctional protein that not only repairs DNA but also controls DNA-binding activity of many transcription factors that may be involved in cancer progression. The ability of the transcription factors p53, nuclear factor B, and activator protein 1 (AP1) to bind to consensus DNA sequences was decreased markedly with zinc deficiency, as assayed by electrophoretic mobility-shift assays. Thus, low intracellular zinc status causes oxidative DNA damage and induces DNA-repair protein expression, but binding of p53 and important downstream signals leading to proper DNA repair are lost without zinc.

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Esophageal Cancer Prevention in Zinc-Deficient Rats: Rapid Induction of Apoptosis by Replenishing Zinc

Abstract: Zinc replenishment of NMBA-treated ZD rats rapidly induces apoptosis in esophageal epithelial cells and thereby substantially reduces the development of esophageal cancer.

Cited by 74 publications

References 29 publications

Prevention of upper aerodigestive tract cancer in zinc‐deficient rodents: Inefficacy of genetic or pharmacological disruption of COX‐2

Prevention of upper aerodigestive tract cancer in zinc‐deficient rodents: Inefficacy of genetic or pharmacological disruption of COX‐2

Heme iron, zinc and upper digestive tract cancer: The Iowa Women's Health Study

Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFκB, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line

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