Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most common metabolic hallmark of malignant tumors, i.e., the "Warburg effect" is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen. The pivotal player in this frequent cancer phenotype is mitochondrial-bound hexokinase [Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 1977;74(9):3735-9; Bustamante E, Morris HP, Pedersen PL. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 1981;256(16):8699-704]. Now, in clinics worldwide this prominent phenotype forms the basis of one of the most common detection systems for cancer, i.e., positron emission tomography (PET). Significantly, HK-2 is the major bound hexokinase isoform expressed in cancers that exhibit a "Warburg effect". This includes most cancers that metastasize and kill their human host. By stationing itself on the outer mitochondrial membrane, HK-2 also helps immortalize cancer cells, escapes product inhibition and gains preferential access to newly synthesized ATP for phosphorylating glucose. The latter event traps this essential nutrient inside the tumor cells as glucose-6-P, some of which is funneled off to serve as carbon precursors to help promote the production of new cancer cells while much is converted to lactic acid that exits the cells. The resultant acidity likely wards off an immune response while preparing surrounding tissues for invasion. With the re-emergence and acceptance of both the "Warburg effect" as a prominent phenotype of most clinical cancers, and "metabolic targeting" as a rational therapeutic strategy, a number of laboratories are focusing on metabolite entry or exit steps. One remarkable success story [Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 2004;324(1):269-75] is the use of the small molecule 3-bromopyruvate (3-BP) that selectively enters and destroys the cells of large tumors in animals by targeting both HK-2 and the mitochondrial ATP synthasome. This leads to very rapid ATP depletion and tumor destruction without harm to the animals. This review focuses on the multiple roles played by HK-2 in cancer and its potential as a metabolic target for complete cancer destruction.
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PMID:Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy. 1910 34

Human breast cancer cells (MDA-MB-435s) secrete a nucleoside diphosphate kinase (NDPK-B) as a phosphoprotein capable of converting diphosphate nucleosides to triphosphate nucleotides for one round in the absence of a phosphoryl donor. Incubation of the partially purified NDPK-B (Nm23-H2 by Western blot) from [gamma32P]Pi-labeled cells with non-radioactive ADP results in the formation of [gamma32P]ATP (Proc. West. Pharmacol. Soc. 44: 61-63, 2001). The presence of a secreted protein that can maintain ATP levels in the vicinity of capillary and lymph vessels may support cancer metastasis in several ways based on the known actions of ATP at P2Y receptors: facilitate intravasation of breast cancer cells that migrate from a solid tumor, support their extravasation at a distal site, and stimulate angiogenesis. The putative role of angiostatin (AS) as an ATP-synthase inhibitor led us to test the notion that AS blocks NDPK-B activity. Addition of commercial AS (kringles 1-4) did not alter enzyme activity. However, AS produced by us and never lyophilized, blocked NDPK activity in a dose-dependent fashion consistent with the notion that extracellular ATP generation by tumor cells may be important to the development of metastases. The ability of 0.5 mg/ml angiostatin to block NDPK-B activity to approximately 75% of control activity compared poorly with the polyphenol inhibitors of. The catechin gallates, theaflavins and ellagic acid inhibited NDPK-B completely with the rank order of potency: EA > theaflavins > EGCG > ECG > PAPS. Our results suggest that the biological activity of angiostatin as a putative metastasis inhibitor may be in part the result of nm23 inhibition and that the production, lyophilization, packaging or storage of commercial angiostatin leads to the alteration of its biological activity against NDPK-B. Ellagic acid is a potent (IC50 = 10.5 microM) NDPK-B inhibitor that may prove useful in elucidating the role of cancer-cell secreted NDPK-B in tumor development.
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PMID:Inhibition of Nm23H2 gene product (NDPK-B) by angiostatin, polyphenols and nucleoside analogs. 1954 70

Malignant melanoma is a lethal disease, and the incidence and mortality associated with it are increasing worldwide. It has a significant tendency to develop both metastasis and resistance to chemotherapy. The tumor cells show abnormal redox regulation, and although the molecular mechanisms involved are not well characterized, they seem to be related to oxidative stress. In a previous study, we showed the antitumoral properties of gallic acid ester derivatives in leukemia cells. Here, we show the effect of octyl, decyl, dodecyl and tetradecyl gallates on B16F10 cells, a melanoma cell line. All compounds induced cytotoxic effects, and the IC(50) values obtained were between 7microM and 17microM after 48h of incubation. Cell death occurred through apoptosis, as demonstrated by the genomic DNA fragmentation pattern. The gallates were able to induce significant production of free radicals, deplete both glutathione and ATP, activate NF-kappaB and promote the inhibition of cell adhesion under the experimental conditions. The glutathione depletion induced by these compounds was related to the inhibition of gamma-glutamylcysteine synthase activity. These results suggest that gallates induce tumoral cell death through apoptosis as a consequence of oxidative stress, though they use different mechanisms to do so. These findings are important since melanoma cells are resistant to death because of their high level of antioxidant defense, adhesion capability and propensity to metastasize.
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PMID:Gallic acid ester derivatives induce apoptosis and cell adhesion inhibition in melanoma cells: The relationship between free radical generation, glutathione depletion and cell death. 1957 52

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.
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PMID:Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. 2239 93

Breast cancer resistance protein (BCRP/ABCG2) was discovered in multidrug resistant breast cancer cells having an ATP-dependent transport-based resistance phenotype. This ABC transporter functions (at least in part) as a xenobiotic protective mechanism for the organism: in the gut and biliary tract, it prevents absorption and enhances elimination of potentially toxic substances. As a placental barrier, it protects the fetus; similarly, it serves as a component of blood-brain and blood-testis barrier; BCRP is expressed in stem cells and may protect them from potentially harmful agents. Therefore, BCRP could influence cancer outcomes by (a) endogenous BCRP affecting the absorption, distribution, metabolism, and elimination of anticancer drugs; (b) BCRP expression in cancer cells may directly cause resistance by active efflux of anticancer drugs; (c) BCRP expression in cancer cells could be a manifestation of the activity of metabolic and signaling pathways that impart multiple mechanisms of drug resistance, self-renewal (stemness), and invasiveness (aggressiveness)--i.e. impart a poor prognosis--to cancers. This chapter presents a synopsis of translational clinical studies relating BCRP expression in leukemias, lymphomas, and a variety of solid tumors with clinical outcome. Data are emerging that expression of BCRP, like P-glycoprotein/ABCB1, is associated with adverse outcomes in a variety of human cancers. Whether this adverse prognostic effect results from resistance imparted to the cancer cells as the direct result of BCRP efflux of anticancer drugs, or whether BCRP expression (and also Pgp expression - coexpression of these transporters is common among poor risk cancers) serves as indicators of the activity of signaling pathways that enhance cancer cellular proliferation, metastases, genomic instability, enhance drug resistance, and oppose programmed cell death mechanisms is yet unknown.
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PMID:Impact of breast cancer resistance protein on cancer treatment outcomes. 1994 28

Clinicians successfully utilize high uptake of radiolabeled glucose via PET scanning to localize metastases in melanoma patients. To take advantage of this altered metabolome, 3-bromopyruvate (BrPA) was used to overcome the notorious resistance of melanoma to cell death. Using four melanoma cell lines, BrPA triggered caspase independent necrosis in two lines, whilst the other two lines were resistant to killing. Mechanistically, sensitive cells differed from resistant cells by; constitutively lower levels of glutathione, reduction of glutathione by BrPA only in sensitive cells; increased superoxide anion reactive oxygen species, loss of outer mitochondrial membrane permeability, and rapid ATP depletion. Sensitive cell killing was blocked by N-acetylcysteine or glutathione. When glutathione levels were reduced in resistant cell lines, they became sensitive to killing by BrPA. Taken together, these results identify a metabolic-based Achilles' heel in melanoma cells to be exploited by use of BrPA. Future pre-clinical and clinical trials are warranted to translate these results into improved patient care for individuals suffering from metastatic melanoma.
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PMID:3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines. 2043 10

Transforming growth factor-beta (TGF-beta) signals are closely associated with the distant metastases of gastric cancer. The aim of this study was to clarify the effect of a TGF-beta receptor I (TbetaR-I) phosphorylation inhibitor, Ki26894, in combination with anticancer drugs, on the lymph node (LN) metastasis of scirrhous gastric cancer. A novel TbetaR-I kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at the ATP binding site of TbetaR-I. S1 is a 5-fluorouracil analog. The human scirrhous gastric cancer cell line OCUM-2MLN and the human gastric fibroblasts NF-33 were used. OCUM-2MLM cells in the upper well and NF-33 cells in the lower well were co-incubated with or without Ki26894. The proliferation of OCUM-2MLN cells was significantly stimulated by co-culture with NF-33 cells. Ki26894 significantly suppressed the growth interactions between OCUM-2MLN cells and NF-33 cells. Gastric cancer models established by orthotopic inoculation of OCUM-2MLN cells showed diffusely infiltrating gastric adenocarcinoma accompanied by LN metastases. We divided these mice into four groups, (control vehicle, Ki26894, S1, Ki26894 plus S1), and examined the effect of Ki26894 and/or S1 on phosphorylation of Smad2, tumor size, LN metastases, and lymphatic involvements. Ki26894 inhibited the Smad2 phosphorylation of cancer cells and decreased the extent of lymphatic involvement, compared with the control or S1 only group. The Ki26894 plus S1 administration group significantly suppressed tumor growth and decreased LN metastasis more effectively than either alone. These findings suggested that the TbetaR-I kinase inhibitor with S1 is useful for the treatment of scirrhous gastric carcinoma with LN metastasis. (Cancer Sci 2010).
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PMID:Combination effect of a TGF-beta receptor kinase inhibitor with 5-FU analog S1 on lymph node metastasis of scirrhous gastric cancer in mice. 2051 90

The value of cross-sectional liver imaging is evaluated by the accuracy, sensitivity, and specificity of the specific imaging technique. Magnetic resonance imaging (MRI) has become a key technique for the characterization and detection of focal and diffuse liver disease. More recently, gadoxetic acid, the hepatocyte-specific MR contrast agent, was clinically approved and introduced in many countries. Gadoxetic acid may be considered a "molecular imaging" probe because the compound is actively taken into hepatocytes via the ATP-dependent organic anion transport system in the plasma membrane for the hepatic uptake. The transport of gadoxetic acid from the cytoplasm to the bile is mainly determined by the capacity of the transport protein glutathione-S-transferase. Gadoxetic acid enhances hepatocyte-containing lesions and improves detection of lesions devoid of normal hepatocytes, such as metastases. Innovative rapid MR acquisition techniques with near isotropic 3D pulse sequences with fat saturation parallel the technical progress made by multidetector computed tomography combined with an impressive improvement in tumor-liver contrast when used for gadoxetic acid-enhanced MRI. The purpose of this review is to provide an overview of the development, clinical testing, and applications of this novel MR contrast agent.
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PMID:Detection and characterization of liver lesions using gadoxetic acid as a tissue-specific contrast agent. 2071 57

ATP-gated P2X(7) receptors (P2X(7)R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X(7)R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X(7)R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X(7) receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca(2+)-activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X(7)R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X(7)R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X(7)R antagonists.
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PMID:P2X(7) receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness. 2124 69

The success of some chemo- and radiotherapeutic regimens relies on the induction of immunogenic tumor cell death and on the induction of an anticancer immune response. Cells succumbing to immunogenic cell death undergo specific changes in their surface characteristics and release pro-immunogenic factors according to a defined spatiotemporal pattern. This stimulates antigen presenting cells such as dendritic cells to efficiently take up tumor antigens, process them, and cross-prime cytotoxic T lymphocytes, thus eliciting a tumor-specific cognate immune response. Such a response can also target therapy-resistant tumor (stem) cells, thereby leading, at least in some instances, to tumor eradication. In this review, we shed some light on the molecular identity of the factors that are required for cell death to be perceived as immunogenic. We discuss the intriguing observations that the most abundant endoplasmic reticulum protein, calreticulin, the most abundant intracellular metabolite, ATP, and the most abundant non-histone chromatin-binding protein, HMGB1, can determine whether cell death is immunogenic as they appear on the surface or in the microenvironment of dying cells.
Cancer Metastasis Rev 2011 Mar
PMID:Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy. 2124 25


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