Poster 3: Immunohistochemical Characterization of Nitric Oxide Synthase in Squamous Cell Carcinoma of the Head and Neck

Rosbe, Kristina W.; Weissler, Mark C.; Prazma, Jiri; Petrusz, Peter; Mims, James W.; Ball, S.

doi:10.1016/s0194-5998(05)80638-2

Cited by 35 publications

(57 citation statements)

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“…As indicated in our prior works, a number of tumor cell lines have been adapted to HNO concentration levels including those from lung [11,[46][47][48], head and neck [3,[49][50][51][52], and breast [7], suggesting that NO adaptation is also a universal property. In an attempt to further elucidate the impact of extended exposure from NO on underlying biological systems, we herein characterize the four newly The ten most up-regulated appear first and the ten most down-regulated appear below within each cell line type NA not available a Gene symbols used vary according to the supplier of the gene chip created breast adenocarcinoma HNO cell lines [7], along with each respective parent cell line.…”

Section: Resultsmentioning

confidence: 85%

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

et al. 2012

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There is a lack of understanding of the casual mechanisms behind the observation that some breast adenocarcinomas have identical morphology and comparatively different cellular growth behavior. This is exemplified by a differential response to radiation, chemotherapy, and other biological intervention therapies. Elevated concentrations of the free radical nitric oxide (NO), coupled with the upregulated enzyme nitric oxide synthase (NOS) which produces NO, are activities which impact tumor growth. Previously, we adapted four human breast cancer cell lines: BT-20, Hs578T, T-47D, and MCF-7 to elevated concentrations of nitric oxide (or high NO [HNO]). This was accomplished by exposing the cell lines to increasing levels of an NO donor over time. Significantly, the HNO cell lines grew faster than did each respective ("PARENT") cell line even in the absence of NO donor-supplemented media. This was evident despite each "parent" being morphologically equivalent to the HNO adapted cell line. Herein, we characterize the HNO cells and their biological attributes against those of the parent cells. Pairs of HNO/parent cell lines were then analyzed using a number of key cellular activity criteria including: cell cycle distribution, DNA ploidy, response to DNA damage, UV radiation response, X-ray radiation response, and the expression of significant cellular enzymes. Other key enzyme activities studied were NOS, p53, and glutathione S-transferase-pi (GST-pi) expression. HNO cells were typified by a far more aggressive pattern of growth and resistance to various treatments than the corresponding parent cells. This was evidenced by a higher S-phase percentage, variable radioresistance, and up-regulated GST-pi and p53. Taken collectively, this data provides evidence that cancer cells subjected to HNO concentrations become resistant to free radicals such as NO via up-regulated cellular defense mechanisms, including p53 and GST-pi. The

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Section: Resultsmentioning

confidence: 85%

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

et al. 2012

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“…In human ovarian cancer, iNOS activity has been localized in tumour cells and not found in normal tissue [16]. Other tumours that have demonstrated iNOS gene expression are brain [1][34], head and neck [35], esophagus [36], lung [37], prostate [38], bladder [39], pancreatic [40], and Kaposi s sarcoma [41].…”

Section: Nitric Oxide Synthase Expression In Tumoursmentioning

confidence: 99%

The role of nitric oxide in cancer

Liu

Loizidou³

et al. 2002

Cell Res

693

500

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Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties. Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53, poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understanding at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.

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“…In addition, knowledge gained of the enzyme(s) involved in drug reduction and toxicity would provide an ideal means of identifying tumors that are likely to be responsive to the drug. The high incidences of tumor nitric oxide synthase (NOS) expression reported in many clinical studies (Thomsen et al, 1994(Thomsen et al, , 1995Cobbs et al, 1995;Rosbe et al, 1995;Gallo et al, 1999;Swana et al, 1999), strongly suggest that NOS is widely expressed and often up-regulated in multiple tumor tissues. Hence, it presents an attractive target to improve cancer therapy.…”

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confidence: 99%

Non-Nuclear Localized Human NOSII Enhances the Bioactivation and Toxicity of Tirapazamine (SR4233) in Vitro

Chinje

Cowen²,

Feng³

et al. 2003

Mol Pharmacol

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Tirapazamine (TPZ) is the lead member of a class of bioreductive drugs currently in phase II and III clinical trials. TPZ requires metabolic activation to give a cytotoxic free radical species, and this hypoxia-mediated process is carried out by a variety of cellular reductases, including NADPH cytochrome c (P450) reductase (P540R). Nitric-oxide synthase (NOS) is widely expressed in human tumors, and this enzyme consists of an oxidase and a reductase domain, the latter showing striking homology to P450R. Thus, in this article, we have investigated the role of one of the cytosolic isoforms of NOS [inducible NOS (NOSII)] in the bioactivation of this DNA-damaging antitumor agent. To achieve this, we have constitutively overexpressed NOSII in human breast tumor MDA231 cells by employing an optimized expression vector in which the strong human polypeptide chain elongation factor 1␣ promoter drives a bicistronic message encoding the genes for human NOSII and the puromycin-resistant gene (pac). Subcellular localization of NOSII in the stably transfected clones was determined after differential centrifugation and showed that NOSII catalytic activity was exclusively cytosolic as determined by conventional activity assay. This was confirmed by immunostaining followed by fluorescent microscopy studies. The increase in NOSII activity in a series of transfected clones was associated with an increase in TPZ metabolism and toxicity under hypoxic conditions. There was no similar increase in aerobic toxicity. These findings are of significance for two reasons. First, cellular NOSII activity, similar to that seen in human breast cancer, could contribute to TPZ toxicity; second, this will be a result of NOSderived/cytosol-associated TPZ radicals.Tirapazamine 2, SR 4233, Tirazone)] is a promising antitumor agent that has a unique spectrum of activity in that it selectively causes DNA damage in hypoxic tumor cells after one-electron bioreductive activation. Cytotoxicity results from activation by a reductive enzyme(s) that adds an electron to the parent drug to produce radical species that cause DNA single-strand breaks, double-strand breaks (DSBs), and chromosome aberrations (Wang et al

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Poster 3: Immunohistochemical Characterization of Nitric Oxide Synthase in Squamous Cell Carcinoma of the Head and Neck

Cited by 35 publications

References 0 publications

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

The role of nitric oxide in cancer

Non-Nuclear Localized Human NOSII Enhances the Bioactivation and Toxicity of Tirapazamine (SR4233) in Vitro

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