Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia exists in solid tumor tissues due to abnormal vasculature, vascular insufficiency, treatment or malignancy related anemia, and low intratumor blood flow. Hypoxic status in solid tumor promotes accumulation of hypoxia-inducible factor-1 alpha which is promptly degraded by proteasomal ubiquitination under normoxic conditions. However, under hypoxic conditions, the ubiquitination system for HIF-1 alpha is inhibited by inactivation of prolyl hydroxylase which is responsible for hydroxylation of proline in the oxygen-dependent degradation domain of HIF-1 alpha. HIF-1 alpha is an important transcriptional factor that codes for hundreds of genes involved in erythropoiesis, angiogenesis, induction of glycolytic enzymes in tumor tissues, modulation of cancer cell cycle, cancer proliferation, and cancer metastasis. Hypoxia and accumulation of HIF-1 alpha in solid tumor tissues have been reported to associate with resistance to chemotherapy, radiotherapy, and immunotherapy and poor prognosis. Production of vascular endothelial growth factor (VEGF) in cancer cells is regulated by the activated HIF-1 mediated system. An increase in VEGF levels subsequently induces HIF-1 alpha accumulation and promotes tumor metastasis by angiogenesis. Recently, angiogenesis targeting therapy using humanized VEGF antibody and VEGF receptor tyrosine kinase inhibitors have been used in solid cancer therapy. Nitric oxide (NO) is a unique chemical gaseous molecule that plays a role as a chemical messenger involved in vasodilator, neurotransmitter, and anti-platelet aggregation. In vivo, NO is produced and released from three different isoforms of NO synthase (NOS) and from exogenously administered NO donors. In cancer science, NO has been mainly discussed as an oncogenic molecule over the past decades. However, NO has recently been noted in cancer biology associated with cancer cell apoptosis, cancer cell cycle, cancer progression and metastasis, cancer angiogenesis, cancer chemoprevention, and modulator for chemo/radio/immuno-therapy. The presence and activities of all the three isoforms of NOS and were detected in cancer tissue components such as cancer cells, tumor-associated macrophages, and vascular endothelium. Overexpression of iNOS in cancer tissues has been reported to associate with poor prognosis in patients with cancers. On the other hand, NO donors such as nitroglycerin have been demonstrated to improve the effects of cancer therapy in solid cancers. Nitroglycerin has been used safely for a long time as a potent vasodilator for the treatment of ischemic heart diseases or heart failure. Therefore, we think highly of clinical use of nitroglycerin as a novel cancer therapy in combination with anticancer drugs for improvement of cancer therapeutic levels. In this review article, we demonstrate the unique physiological characteristics of malignant solid tumors, several factors in solid tumors resulting in resistance for cancer therapies, and the effects of NO from NOS or exogenous NO-donating drugs on malignant cells. Furthermore, we refer to promising therapeutic roles of NO and NO-donating drugs for novel treatments in solid tumors.
Nitric Oxide 2008 Sep
PMID:Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer. 1850 79

Highly metastatic cells, especially in the lungs, are known to be resistant to nitric oxide (NO)-mediated cytotoxicity, compared with poorly or non-metastatic cells. However, the precise mechanisms connecting NO and metastasis remain to be determined. To clarify the role of NO in the characteristic changes in NO-resistant cells in response to inflammatory cytokines, we used Lewis lung tumor (LLT) cells, which are known to be highly metastatic NO-resistant cells, and determined the changes in cell deformability and the gene expression profile after the cells were stimulated using cytokine mixture or an NO donor. Both exogenous NO and endogenous NO via inducible NO synthase produced by cytokines decreased cell deformability by enhancing actin polymerization. The expression of several genes associated with actin polymerization was changed so as to increase actin filaments in the cells by enhancing actin polymerization and by suppressing actin depolymerization, actin filament severing, and barbed-end actin filament capping. In conclusion, inflammatory cytokine stimulation reduces deformability of LLT cells and enhances actin polymerization which is mainly controlled by the same genes induced by NO.
Nitric Oxide 2008 Dec
PMID:The role of nitric oxide in reducing deformability of Lewis lung tumor cell stimulated by inflammatory cytokines. 1872 44

Treatment of TRAIL-resistant tumor cells with the nitric oxide donor DETANONOate sensitizes the tumor cells to TRAIL-induced apoptosis concomitantly with DR5 upregulation. The mechanism of sensitization was examined based on the hypothesis that DETANONOate inhibits a transcription repressor Yin Yang 1 (YY1) that negatively regulates DR5 transcription. Treatment of the prostate carcinoma cell lines with DETANONOate inhibited both NF-kappaB and YY1 DNA-binding activities concomitantly with upregulation of DR5 expression. The direct role of YY1 in the regulation of TRAIL resistance was demonstrated in cells treated with YY1 siRNA resulting in TRAIL-induced apoptosis. The role of YY1 in the transcriptional regulation of DR5 was examined in cells treated with a DR5 luciferase reporter system (pDR5) and two constructs, namely, the pDR5/-605 construct with a deletion of the putative YY1 DNA-binding region (-1224 to -605) and a construct pDR5-YY1 with a mutation of the YY1 DNA-binding site. A significant (3-fold) augmentation of luciferase activity over baseline transfection with pDR5 was observed in cells transfected with the modified constructs. ChIP analysis corroborated the YY1 binding to the DR5 promoter. In vivo, tissues from nude mice bearing the PC-3 xenograft and treated with DETANONOate showed inhibition of YY1 and upregulation of DR5. The present findings demonstrate that YY1 negatively regulates DR5 transcription and expression and these correlated with resistance to TRAIL-induced apoptosis. DETANONOate inhibits both NF-kappaB and YY1 and in combination with TRAIL reverses tumor cell resistance to TRAIL apoptosis.
Nitric Oxide 2009 Feb
PMID:Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1. 1877 87

Tumor cells develop mechanisms that dysregulate apoptotic pathways resulting in resistance to cytotoxic stimuli. Primary SW480 and metastatic SW620 colon cancer cells are resistant to CDDP-induced apoptosis. Apoptosis-inducing factor (AIF) was significantly downregulated in SW620 compared to SW480 cells; while apoptotic mediators such as Bax, Bcl-2, and Bcl(XL) were not altered in these cell lines. Examination of tumor tissues from patients with colon cancer demonstrated a significant downregulation of AIF in patients with advanced disease. The role of AIF expression in resistance was examined. Several lines of evidence suggest the involvement of AIF expression level in the sensitivity of SW620 to CDDP-induced apoptosis: (1) sensitization of SW620 by the NO donor DETANONOate to CDDP-induced apoptosis correlated with the induction of AIF as assessed by RT-PCR and Western blot analysis, (2) treatment of SW620 cells with siRNA AIF, but not with control siRNAs, inhibited DETANONOate-induced sensitization to CDDP apoptosis, (3) sensitization by DETANONOate observed in vitro was corroborated in vivo in nude mice bearing SW620 tumor xenografts and treated with the combination of DETANONOate and CDDP, and (4) tumor tissues derived from the SW620 xenografts revealed significant upregulation of AIF and increased apoptosis by DETANONOate and CDDP combination treatment. Altogether, these findings underscore the potential therapeutic application of NO donors and subtoxic chemotherapeutic drugs in the treatment of advanced colon cancer resistant to conventional chemotherapeutic agents.
Nitric Oxide 2009 May
PMID:In vitro and in vivo sensitization of SW620 metastatic colon cancer cells to CDDP-induced apoptosis by the nitric oxide donor DETANONOate: Involvement of AIF. 1910 80

Exogenous NO donor 3,3-bis-(nitroxymethyl)oxetane (NMO) was synthesized at the Institute for Problems of Chemical Physics (Russian Academy of Sciences). This compound was shown to inhibit Ca2+-ATPase isolated from normal muscular cells and tumor cells. Both hydrolytic and transport functions of the enzyme were inhibited under these conditions. These changes were probably related to changes in membrane structure caused by NO donor. Our results suggest that changes in intracellular Ca2+ concentration can modulate the formation of tumor drug resistance.
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PMID:Effect of drug resistance modulator, NO donor, on membrane structure and function of membrane-bound Ca2+-activated Mg2+-dependent ATPase. 1914 17

Neuromyelitis optica is associated with antibodies to aquaporin-4 channels and has been classically defined as the occurrence of bilateral optic neuritis and transverse myelitis with no other neurological involvement. We describe here a 63-year-old woman who presented to our local hospital with an acute, bilateral visual loss followed by progressive paraparesis. Medical evaluations revealed a lung tumor and spinal MRI showed multiple cervical-dorsal hyperintense T(2) lesions with mild mass effect. Testing for NMO-Ig resulted positive. Patient's diagnosis was thus consistent with a possible paraneoplastic neuromyelitis optica associated with non-small cell lung cancer and evidence of NMO-Ig.
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PMID:A possible paraneoplastic neuromyelitis optica associated with lung cancer. 1956 83

Exogenous NO donor 3,3-bis-(nitroxymethyl)oxetane (NMO) was synthesized at the Institute for Problems of Chemical Physics (Russian Academy of Sciences). This compound was shown to inhibit cell death (apoptosis and necrosis) in cyclophosphamide-sensitive and cyclophosphamide-resistant P388 murine tumor. p53 protein was expressed in both lines of tumor cells. NO donor NMO had little effect on p53 protein expression in cells of both stains. Our results suggest that the proapoptotic effect of NMO is mediated by the p53-independent molecular mechanisms.
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PMID:Effect of nitric oxide donor, a modulator of tumor drug resistance, on cell death and p53 protein expression. 1970 38

Recently, nitric oxide has been investigated as a potential anti-cancer therapy because of its cytotoxic activity. Previously, we found that S-nitrosylated human serum albumin (SNO-HSA) induced apoptosis in C26 cells, demonstrating for the first time that SNO-HSA has potential as an anti-cancer drug. In the present study, the anti-tumor activity of SNO-HSA in another tumor type of cancer cell was investigated using murine tumor LY-80 cells. Mitochondrial depolarization, activation of caspase-3 and DNA fragmentation were induced in LY-80 cells by SNO-HSA treatment in a dose-dependent manner. Inhibition of caspase activity resulted in complete inhibition of DNA fragmentation induced by SNO-HSA. The cytotoxic effects of SNO-HSA on LY-80 were concentration-dependent. Tumor growth in LY-80-tumor-bearing rats was significantly inhibited by administration of SNO-HSA compared with saline- and HSA-treatment. These results suggest that SNO-HSA has potential as a chemopreventive and/or chemotherapeutic agent because it induces apoptosis in tumor cells.
Nitric Oxide 2010 May 15
PMID:Nitrosylated human serum albumin (SNO-HSA) induces apoptosis in tumor cells. 2060 23

Our previous studies demonstrate a differential expression of nitric oxide (NO) signaling components in ES cells and our recent study demonstrated an enhanced differentiation of ES cells into myocardial cells with NO donors and soluble guanylyl cyclase (sGC) activators. Since NO-cGMP pathway exhibits a diverse role in cancer, we were interested in evaluating the role of the NO-receptor sGC and other components of the pathway in regulation of the tumor cell proliferation. Our results demonstrate a differential expression of the sGC subunits, NOS-1 and PKG mRNA and protein levels in various human cancer models. In contrast to sGC alpha(1), robust levels of sGC beta(1) were observed in OVCAR-3 (ovarian) and MDA-MB-468 (breast) cancer cells which correlated well with the sGC activity and a marked increase in cGMP levels upon exposure to the combination of a NO donor and a sGC activator. NOC-18 (DETA NONOate; NO donor), BAY41-2272 (3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine); sGC activator), NOC-18+BAY41-2272, IBMX (3-isobutyl-1-methylxanthine; phosphodiesterase inhibitor) and 8-bromo-cGMP (cGMP analog) caused growth inhibition and apoptosis in various cancer cell lines. To elucidate the molecular mechanisms involved in growth inhibition, we evaluated the effect of activators/inhibitors on ERK phosphorylation. Our studies indicate that BAY41-2272 or the combination NOC-18+BAY41-2272 caused inhibition of the basal ERK1/2 phosphorylation in OVCAR-3 (high sGC activity), SK-OV-3 and SK-Br-3 (low sGC activity) cell lines and in some cases the inhibition was rescued by the sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). These studies suggest that the effects of activators/inhibitors of NO-sGC-cGMP in tumor cell proliferation is mediated by both cGMP-dependent and independent mechanisms.
Nitric Oxide 2010 Jan 01
PMID:Role of soluble guanylyl cyclase-cyclic GMP signaling in tumor cell proliferation. 1994 39

The benzoquinone derivative embelin is a multifunctional drug that not only induces apoptosis by inhibiting XIAP, the X chromosome-linked inhibitor of apoptosis protein, but also blocks nuclear factor-kappaB signaling pathways, thereby leading to down-regulation of a variety of gene products involved in tumor cell survival, proliferation, invasion, angiogenesis, and inflammation. Here, we report that embelin activates and modulates l-arginine/nitric oxide/cyclic GMP signaling in cultured endothelial cells. Embelin elicited a rapid increase of intracellular free Ca(2+), leading to activation of endothelial nitric oxide synthase (eNOS) and NO-induced cGMP accumulation. While the cGMP response was comparable to that caused by other Ca(2+)-mobilizing agents, the stimulatory effect of embelin on l-citrulline formation (approximately 4-fold) was substantially lower than that observed upon activation of eNOS with the Ca(2+) ionophore A23187 (approximately 18-fold), the receptor agonist ATP (approximately 16-fold) or the sarco-endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (approximately 14-fold). The apparent discrepancy between NO/cGMP and l-citrulline formation in embelin-treated cells was not due to enhanced metabolism and/or efflux of l-citrulline, increased NO bioavailability, inhibition of cGMP hydrolysis, sensitization of soluble guanylate cyclase (sGC) to NO, or enhanced formation of a sGC/eNOS complex. Our puzzling observations suggest that embelin improves coupling of endothelial NO synthesis to sGC activation through mobilization of an as yet unrecognized signaling pathway.
Nitric Oxide 2010 May 15
PMID:Activation of endothelial nitric oxide synthase by the pro-apoptotic drug embelin: Striking discrepancy between nitric oxide-mediated cyclic GMP accumulation and L-citrulline formation. 2014 27


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