Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-α transgenic mouse model of liver cancer

Calvisi, Diego F.; Ladu, Sara; Hironaka, Koji; Factor, Valentina M.; Thorgeirsson, Snorri S.

doi:10.1016/j.jhep.2004.07.030

Cited by 85 publications

(51 citation statements)

References 42 publications

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“…In addition to telomere shortening, other mechanisms such as genomic hypomethylation and hypermethylation, oxida- tive and nitrosative DNA damage, and a defective DNA repair system appear to contribute to the development of CIN in HCC. 4,[17][18][19] The stepwise increase of CIN seems to be in line with the accumulation of genetic alterations involving proto-oncogenes and tumor suppressor genes such as p53, Rb1, EXT1, APC, nm23, DCC, BRCA1, VHL, DPC4, and WT1. 4,[20][21][22][23][24] Gains at 8q22-24 correlate with overexpression of the c-myc gene, found in most of the liver cancers.…”

Section: Discussionmentioning

confidence: 90%

Telomere Shortening Correlates With Increasing Aneuploidy of Chromosome 8 in Human Hepatocellular Carcinoma *

et al. 2005

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Chromosomal instability (CIN) leads to an increase in aneuploidy and chromosomal aberrations in human hepatocellular carcinoma (HCC). Telomere shortening appears as one mechanism fostering the development of CIN. Whether telomere shortening correlates to specific genetic changes that characterize a certain type of cancer has yet to be established. In our recent study, we combined on a cellular level the analysis of hepatocellular telomere fluorescent intensity (TFI) and copy number of chromosome 8 -one of the hallmark chromosomal alterations in hepatocellular carcinoma (HCC). We investigated 15 cytological fine-needle biopsies of aneuploid HCC and 5 touch prints of cadaver livers without cancer. Hepatocyte-specific TFI and the measurement of centromere-specific probe for chromosome 8 were both performed by quantitative fluorescence in situ hybridization (qFISH) or FISH. Combined analysis of both methods (coFISH) allowed measurement of telomere length and chromosome 8 copy number on a single cell level. We observed that telomere shortening correlates significantly with increasing copy number of chromosome 8 in HCC on the cellular level. Above the level of 5 copies of chromosome 8 per nucleus, no further shortening of telomeres was found, indicating that telomeres had reached a critically short length at this stage of aneuploidy. In conclusion, our study gives direct evidence that telomere shortening is linked to a specific genetic alteration characteristic for human HCC. (HEPATOLOGY 2005;42: 522-526.)H epatocellular carcinoma (HCC) is a common tumor worldwide. 1,2 One of the common features of human epithelial cancer including HCC is the prevalence of chromosomal instability (CIN). [3][4][5][6] The molecular mechanisms that lead to induction of CIN are still under debate. 7 Telomere shortening has been proposed as one of the mechanisms fostering CIN during aging and chronic disease. 3 We have recently demonstrated that telomere shortening characterizes hepatocytes of HCC compared with hepatocytes in regenerative nodules or surrounding noncancerous liver tissue. 8 Whether telomere shortening simply leads to random genomic instability or whether it leads to specific cytogenetic changes reflecting the cytogenetic fingerprint of a specific tumor type remains to be determined. In more than 90% of all HCC, chromosomal aberrations can be detected by using centromere-specific chromosome probes for chromosomes 1 and 8, indicating the significant role of CIN in the development of HCC. 9,10 To test whether telomere shortening correlates with the accumulation of cancer-specific genetic alteration in HCC, we analyzed telomere fluorescent intensity (TFI) and copy number of chromosome 8 using a newly developed coFISH (fluorescence in situ hybridization) technique combining telomere-specific quantitative FISH (qFISH) and chromosome 8 -specific centromere labeling.Our data give experimental evidence that telomere shortening in human HCC is not only linked to random From the

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Section: Discussionmentioning

confidence: 90%

Telomere Shortening Correlates With Increasing Aneuploidy of Chromosome 8 in Human Hepatocellular Carcinoma *

et al. 2005

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“…Moreover, animal models of hepatocarcinogenesis induction mostly have ROS production in common, despite of the cellular targets or cytotoxic effects [19]. In fact, tumor growth inhibition has been described to occur upon antioxidants dietary supplementation in animal models [20]. Moreover, a NADPH oxidase system-derived ROS production has been proposed as main mediator in hepatocarcinogenic processes occurring in different animal models, such as the TGF-alpha/c-myc transgenic mice [20], or exposure to carcinogens such as diethylnitrosamine [21].…”

Section: Discussionmentioning

confidence: 99%

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Sancho

Fabregat

2011

Biochemical Pharmacology

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This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25 M. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-(Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer.

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“…These findings suggest that nitric oxide produced by iNOS may be involved in prostate tumorigenesis (53). In addition, Calvisi et al revealed that iNOS and NADPH oxidase were involved in ROS generation during c-Myc/transforming growth factor a hepatocarcinogenesis and were inhibited by antioxidant agent treatment (54).…”

Section: Mol Cancer Res 2008;6(2) February 2008mentioning

confidence: 97%

Angiotensin II Induces Oxidative Stress in Prostate Cancer

Uemura

Ishiguro

et al. 2008

Molecular Cancer Research

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Angiotensin II has been shown to be a cytokine especially acting as a growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of angiotensin II seems to be similar in prostate cancer, as we previously reported. In the present study, we explored the biological role of angiotensin II in oxidative stress of prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related proteins (p47phox, manganese superoxide dismutase 2, glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with angiotensin II and/or an angiotensin II receptor type 1 blocker, candesartan. To examine DNA damage induced by angiotensin II, 8-hydroxy-2 ¶-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint proteins including p53, Chk2, and cdc2. Immunocytochemical studies of inducible nitric oxide synthase and superoxide anion radical (O 2 À ) were done in LNCaP cells stimulated with angiotensin II. The phosphorylation of Akt was induced by angiotensin II treatment and inhibited by candesartan, as well as by LY294002, an inhibitor of phosphoinositide 3-kinase. Oxidative stress-related proteins were up-regulated by angiotensin II and inhibited by pretreatment with candesartan or catalase. The level of 8-hydroxy-2 ¶-deoxyguanosine was increased by angiotensin II and conversely decreased by candesartan. Immunocytochemical studies showed that angiotensin II enhanced an inflammatory marker, inducible nitric oxide synthase, and the production of O 2 À radical. The hypothesis that angiotensin II has the potential to induce oxidative stress, which may be implicated in carcinogenesis of the prostate gland through long-term exposure to chronic inflammation is proposed. (Mol Cancer Res 2008;6(2):250 -8)

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Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-α transgenic mouse model of liver cancer

Cited by 85 publications

References 42 publications

Telomere Shortening Correlates With Increasing Aneuploidy of Chromosome 8 in Human Hepatocellular Carcinoma *

Telomere Shortening Correlates With Increasing Aneuploidy of Chromosome 8 in Human Hepatocellular Carcinoma *

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Angiotensin II Induces Oxidative Stress in Prostate Cancer

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