Inducible nitric oxide synthase (iNOS) in tumor biology: The two sides of the same coin

Lechner, Matthias; Lirk, Philipp; Rieder, Josef

doi:10.1016/j.semcancer.2005.04.004

Cited by 366 publications

(278 citation statements)

References 156 publications

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“…However, in some circumstances, NO may also lead to tumor expansion and metastases (1,3,4). The outcome of tumor-NO interactions depends on the source and quantity of NO, duration of the exposure, and characteristics of the cells (1).…”

Section: Introductionmentioning

confidence: 99%

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Maksimović‐Ivanić

Mijatović

Harhaji

et al. 2008

Molecular Cancer Therapeutics

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Preclinical studies have shown that nitric oxide (NO) -donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NOdeprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatinresistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.

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Section: Introductionmentioning

confidence: 99%

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Maksimović‐Ivanić

Mijatović

Harhaji

et al. 2008

Molecular Cancer Therapeutics

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“…NO in cancer exhibits both a cytotoxic and a cytoprotective effect according to its concentration within the tumor microenvironment. Low levels of NO produced by tumor cells themselves aid tumor progression, while the high level of NO produced by tumor adjacent macrophages function as a tumor suppressor agent through the induction of apoptosis [4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

Mohamad¹,

Cricco²,

Sambuco³

et al. 2009

WJG

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AIM:To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation, apoptosis, redox status and vascularization. METHODS:Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups: control and aminoguanidine treated. Tumor growth, survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS), catalase, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally, vascularization was determined by Massons trichromic staining, and by VEGF and CD34 expression. RESULTS:Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells, intratumoral vascularization (trichromic stain) and the expression of Ki-67, Bax, eNOS, CD34, VEGF, catalase, CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01), while the expression of Bcl-2 and GPx did not change. C O N C L U S I O N :T h e a n t i t u m o r a l a c t i o n o f aminoguanidine is associated with decreased cell proliferation, reduced angiogenesis, and reduced expression of antioxidant enzymes.

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“…As isoformas "constitutiva" e "induzível" compartilham uma homologia de cerca de 50% dos aminoácidos Grupta, 2011). Todas as isoformas dependem do substrato L-arginina e dos cofatores/coenzimas NADPH, BH4, FAD, FMN, oxigênio e protoporfirina IX para sintetizar NO (Lechner et al, 2005).…”

Section: óXido Nítrico Sintase Induzível (Inos)unclassified

“…O papel do NO no câncer é incerto; ele pode tanto estimular como inibir a progressão tumoral, dependendo da atividade e localização das suas isoformas, da sua concentração, bem como do tempo de exposição e da sensibilidade da célula tumoral (Lechner et al, 2005). A concentração de NO parece ser um fator chave na ação dessa enzima sobre as células tumorais: baixas concentrações (<50 nM) estimulam o crescimento celular e inibem a apoptose; em concentrações intermediárias (entre 100nM e 300nM), há ativação de proteínas que favorecem o crescimento tumoral, como Erk e HIF-1α; já altas concentrações (>300nM) inibem o crescimento e estimulam a apoptose, ativando p53 (Thomas et al, 2004).…”

Section: óXido Nítrico Sintase Induzível (Inos)unclassified

“…O NO está envolvido em diferentes estágios das transformações celulares que levam à malignização, tais como na transformação das células normais por meio da ativação de oncogenes e da perda da atividade anti-oncogênica; no crescimento das células já transformadas por intermédio da indução de desdiferenciação e proliferação; na progressão do tumor a partir de lesões pré-neoplásicas; na angiogênese desencadeada por fatores angiogênicos liberados pelas células tumorais em si ou pelo tecido circundante; e na invasão local e metástase (Fukumura et al, 2006;Lechner et al, 2005).…”

Section: óXido Nítrico Sintase Induzível (Inos)unclassified

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Resistência de células de carcinoma epidermóide bucal à terapia fotodinâmica mediada pelo ácido 5-aminolevulínico

Rosin¹

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A minha Orientadora, Prof a . Dr a . Luciana Corrêa, por sempre ouvir e discutir comigo todas as questões e dúvidas que surgiram durante o desenvolvimento desta tese e por ser essa pessoa tão generosa, inteligente e acessível. Admiro-a muito como pessoa e pesquisadora.Ao Prof. Dr. Moacir Novelli, que durante suas visitas ao laboratório sempre alegrava meu dia e por compartilhar comigo um pouco da sua imensa sabedoria. A Marina, a única companheira de profissão da Pós, que sempre esteve disposta a me ajudar e me ouvir, pela amizade, carinho e companheirismo. Pelos nossos cafés da manhã que sempre tornava meu dia mais leve e agradável.A Karla, pelo bom humor constante que sempre alegrava meu dia, por sempre me ouvir, me apoiar e pelos nossos cafezinhos.A Gabriela, por sempre estar ao meu lado me dando força e apoio, pelos nossos almoços diários na copa do departamento que tornavam meu dia mais alegre e por todo carinho e amizade.A Lara, pela amizade e por todo carinho e apoio. Por ser essa pessoa tão agradável e acessível por sempre estar disposta a me ourvir. Tenho a impressão de ter sido uma criança brincando à beira-mar, divertindo-me em descobrir uma pedrinha mais lisa ou uma concha mais bonita que as outras, enquanto o imenso oceano da verdade continua misterioso diante de meus olhos". Oral squamous cell carcinoma (SCC) is a malignant tumor with high morbidity and mortality rates, and it is difficult to treat. Conventional treatment for oral SCCs includes surgery and radiotherapy that may be followed by chemotherapy. Although these treatments are widely used, they are ineffective against some resistant tumors. Isaac Newton RESUMOOncologic photodynamic therapy (PDT) has been used as an adjuvant treatment for oral SCCs, especially in less invasive cases that require tumor reduction before surgical resection. However, like conventional treatments, PDT can induce the occurrence of resistant cell populations such as cutaneous carcinomas and colon and breast adenocarcinomas. The hypothesis that oral SCCs develop resistance to PDThas not yet been tested. Therefore, the aims of this study were to investigate whether oral SCCs (SCC9) develop resistance to several cycles of 5-aminolevulinic acidmediated PDT (5-ALA-PDT) and to determine whether the expression of markers associated with cell survival (NFB, Bcl-2, iNOS, mTOR, and Akt) is altered during this process. An oral SCC (SCC9) cell line was used, which was subjected to the following conditions: 1) Control: cultured without any treatment; 2) ALA: incubated with 5-ALA (1 mM for 4 h); 3) LED: treated with LED light (630 nm, 5.86 J/cm 2 , 22.5 J, 150 mW, 150 s); and 4) PDT: treated with 5-ALA-PDT (with the protocols of the ALA and LED groups combined) generating a lethal dose of 90%. Initially, only one cycle of PDT was administered, and cell viability was determined in all groups 24, 48, 72, and 120 h after irradiation. Subsequently, the DNA fragmentation detection assay (TUNEL) and immunofluorescence analysis of the expression of proteins NFB, Bcl-2, iNOS, pmTOR, ...

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Inducible nitric oxide synthase (iNOS) in tumor biology: The two sides of the same coin

Cited by 366 publications

References 156 publications

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

Resistência de células de carcinoma epidermóide bucal à terapia fotodinâmica mediada pelo ácido 5-aminolevulínico

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