Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A significant tumor damaging effect (growth inhibition) on transplanted syngeneic sarcoma in mouse was obtained by means of pH-dependent activation of a transport form of a cancerostatic drug by an enzyme foreign to the organism. This effect was achieved by combined administration of 8-0-(alpha-L-arabinofuranosyl)beta-peltatin-A as a transport form of beta-peltatin-A and the exogenous enzyme alpha-L-arabinofuranosidase from Aspergillus niger and additional increase of the acidity of the tumor by injection of glucose. The combined application of the transport form plus enzyme showed a more favorable effect on selectivity than free peltatin when a quantitative comparison was made between the tumor growth inhibition and the damage to the blood picture.
 ...
PMID:Experiments to increase the selectivity of tumor chemotherapy by means of in vivo activation of transport forms of cancerostatics by exogenous enzymes. 2 45

Measurement of pH in tissue has shown that the microenvironment in tumors is generally more acidic than in normal tissues. Major mechanisms which lead to tumor acidity probably include the production of lactic acid and hydrolysis of ATP in hypoxic regions of tumors. Further reduction in pH may be achieved in some tumors by administration of glucose (+/- insulin) and by drugs such as hydralazine which modify the relative blood flow to tumors and normal tissues. Cells have evolved mechanisms for regulating their intracellular pH. The amiloride-sensitive Na+/H+ antiport and the DIDS-sensitive Na+-dependent HCO3-/Cl- exchanger appear to be the major mechanisms for regulating pHi under conditions of acid loading, although additional mechanisms may contribute to acid extrusion. Mitogen-induced initiation of proliferation in some cells is preceded by cytoplasmic alkalinization, usually triggered by stimulation of Na+/H+ exchange; proliferation of other cells can be induced without prior alkalinization. Mutant cells which lack Na+/H+ exchange activity have reduced or absent ability to generate solid tumors; a plausible explanation is the failure of such mutant cells to withstand acidic conditions that are generated during tumor growth. Studies in tissue culture have demonstrated that the combination of hypoxia and acid pHe is toxic to mammalian cells, whereas short exposures to either factor alone are not very toxic. This interaction may contribute to cell death and necrosis in solid tumors. Acidic pH may influence the outcome of tumor therapy. There are rather small effects of pHe on the response of cells to ionizing radiation but acute exposure to acid pHe causes a marked increase in response to hyperthermia; this effect is decreased in cells that are adapted to low pHe. Acidity may have varying effects on the response of cells to conventional anticancer drugs. Ionophores such as nigericin or CCCP cause acid loading of cells in culture and are toxic only at low pHc; this toxicity is enhanced by agents such as amiloride or DIDS which impair mechanisms involved in regulation of pHi. It is suggested that acid conditions in tumors might allow the development of new and relatively specific types of therapy which are directed against mechanisms which regulate pHi under acid conditions.
 ...
PMID:Acid pH in tumors and its potential for therapeutic exploitation. 254 40

In contrast to normal tissues, tumors are exposed to adverse environmental conditions, such as hypoxia and acidity. Despite this caustic environment, tumor cells and supporting vascular structures survive the latter, providing nutrients and oxygen to facilitate tumor growth. Therefore, we hypothesized that cancer cells express factors that protect endothelial cells from apoptosis. Human umbilical vein endothelial cells were grown in serum-free medium or in medium conditioned by either human colon cancer cells or non-malignant cells. Endothelial cells grown in medium conditioned by colon cancer cells demonstrated a decrease in apoptosis, whereas endothelial cells grown in medium conditioned by non-malignant cells did not. Erk-1/2 phosphorylation increased when endothelial cells were incubated in medium conditioned by colon cancer cells but not when cells were incubated in medium conditioned by non-malignant cells. Protein fractions from medium conditioned by colon cancer cells that were < 3 kDa protected endothelial cells from apoptosis and activated Erk-1/2. Heat-inactivated conditioned media did not protect endothelial cells from apoptosis and did not activate Erk-1/2. Human colon cancer cells secrete a soluble factor or factors that inhibit endothelial cell apoptosis. This factor is likely to be a protein or protein fragment because it loses its activity after heat inactivation. These studies support the hypothesis that tumor cells can alter the phenotype of endothelial cells.
 ...
PMID:Endothelial cell apoptosis is inhibited by a soluble factor secreted by human colon cancer cells. 1127 2

The microenvironmental pH and oxygenation is known to influence tumor cell response to heat, radiation, photodynamic and even chemotherapy. We have studied the previously untested influence of acidity and hypoxia on tumor and endothelial cell sensitivity to freezing. In addition, we have measured changes in oxygenation in vivo in murine FSaII fibrosarcomas after freeze injury. A low pH or low oxygenation environment was found to increase the sensitivity of tumor and endothelial cells to freezing at -20 degrees C or -40 degrees C in vitro. However, low pH and low oxygenation combined did not further increase cryosensitivity of the cells. In vivo, tumor oxygenation after freeze injury was studied immediately or 1-3 days after a standard freezing protocol was applied to FSaII tumors ranging from 250-500 mm3 grown in the rear-limb of C3H mice. Tumor oxygenation at the edge of the iceball was found to transiently increase 1-2 hours after freezing. At 1-3 days after freezing, a treatment that delayed FSaII tumor growth by approximately 1.5-fold, the mean tumor oxygenation was significantly increased by up to 2.5-fold from a control level of 5 mmHg partial pressure of oxygen (pO2), especially at the periphery of the tumor. We conclude that manipulation of pH or oxygenation has potential to increase the anti-tumor effects of minimally invasive cryosurgical techniques. Furthermore, the dynamic changes in oxygenation after freeze injury in vivo suggests value in combining cryotherapy with treatments dependent on oxygenation levels. Ultimately, these may be routes to more reliable treatment response with fewer recurrences.
 ...
PMID:Assessing pH and oxygenation in cryotherapy-induced cytotoxicity and tissue response to freezing. 1516 17

Fibroblast activation protein alpha (FAPalpha) is highly expressed in epithelial cancers and has been implicated in extracellular matrix remodeling, tumor growth, and metastasis. We present the first high resolution structure for the apoenzyme as well as kinetic data toward small dipeptide substrates. FAPalpha exhibits a dipeptidyl peptidase IV (DPPIV)-like fold, featuring an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain. Known DPPIV dipeptides are cleaved by FAPalpha with an approximately 100-fold decrease in catalytic efficiency compared with DPPIV. Moreover, FAPalpha, but not DPPIV, possesses endopeptidase activity toward N-terminal benzyloxycarbonyl (Z)-blocked peptides. Comparison of the crystal structures of FAPalpha and DPPIV revealed one major difference in the vicinity of the Glu motif (Glu(203)-Glu(204) for FAPalpha; Glu(205)-Glu(206) for DPPIV) within the active site of the enzyme. Ala(657) in FAPalpha, instead of Asp(663) as in DP-PIV, reduces the acidity in this pocket, and this change could explain the lower affinity for N-terminal amines by FAPalpha. This hypothesis was tested by kinetic analysis of the mutant FAPalpha/A657D, which shows on average an approximately 60-fold increase in the catalytic efficiency, as measured by k(cat)/K(m), for the cleavage of dipeptide substrates. Furthermore, the catalytic efficiency of the mutant is reduced by approximately 350-fold for cleavage of Z-Gly-Pro-7-amino-4-methylcoumarin. Our data provide a clear understanding of the molecular determinants responsible for the substrate specificity and endopeptidase activity of FAPalpha.
 ...
PMID:Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha. 1580 6

The extracellular pH of tumor tissue is significantly lower than the extracellular pH of normal tissue, whereas the intracellular pH of both tissues is similar. In principle, extracellular acidity may be expected to enhance the intracellular uptake and cytotoxicity of weak acid chemotherapeutics that are membrane permeable in their uncharged state and inhibit the efficacy of weak bases. However, procedures for assessing the role of the gradient as a determinant of drug efficacy in vivo by altering the pH gradient may also alter drug availability and thus mask or exaggerate the effect of the gradient change. In the present study, we have altered the extracellular pH of tumors and compared the effect of the resultant pH gradient change on the efficacy of a weak acid versus a weak base. This experimental design gives rise to a change in the ratio of chlorambucil- to doxorubicin-induced tumor growth delay, independent of possible changes in drug availability. The extracellular pH of the 54A human tumor in NCr/Sed/nu/nu mice was altered by administration of 5 mg/g i.v. glucose. The resultant 0.2 pH unit increase in the tumor cell pH gradient gives rise to a predicted 2.3-fold increase in the ratio of chlorambucil to doxorubicin growth delay. The experimentally measured change in the growth delay ratio was 2.1. The results provide compelling evidence that the pH gradient in a determinant of the efficacy of weak electrolytes in the complex in vivo environment and may be exploited for the treatment of cancer.
 ...
PMID:Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. 1673 60

Proton pumps like the vacuolar-type H+ ATPase (V-ATPase) are involved in the control of cellular pH in normal and tumor cells. Treatment with proton pump inhibitors (PPI) induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients. It is also known that low pH is the most suitable condition for a full PPI activation. Here, we tested whether PPI treatment in unbuffered culture conditions could affect survival and proliferation of human B-cell tumors. First, we showed that PPI treatment increased the sensitivity to vinblastine of a pre-B acute lymphoblastic leukemia (ALL) cell line. PPI, per se, induced a dose-dependent inhibition of proliferation of tumor B cells, which was associated with a dose- and time-dependent apoptotic-like cytotoxicity in B-cell lines and leukemic cells from patients with pre-B ALL. The effect of PPI was mediated by a very early production of reactive oxygen species (ROS), that preceded alkalinization of lysosomal pH, lysosomal membrane permeabilization, and cytosol acidification, suggesting an early destabilization of the acidic vesicular compartment. Lysosomal alterations were followed by mitochondrial membrane depolarization, release of cytochrome c, chromatin condensation, and caspase activation. However, inhibition of caspase activity did not affect PPI-induced cell death, whereas specific inhibition of ROS by an antioxidant (N-acetylcysteine) significantly delayed cell death and protected both lysosomal and mitochondrial membranes. The proapoptotic activity of PPI was consistent with a clear inhibition of tumor growth following PPI treatment of B-cell lymphoma in severe combined immunodeficient mice. This study further supports the importance of acidity and pH gradients in tumor cell homeostasis and suggests new therapeutic approaches for human B-cell tumors based on PPI.
 ...
PMID:Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. 1754 22

The acidity of the tumor microenvironment aids tumor growth, and mechanisms causing it are targets for potential therapies. We have imaged extracellular pH (pHe) in C6 cell gliomas in rat brain using 1H magnetic resonance spectroscopy in vivo. We used a new probe molecule, ISUCA [(+/-)2-(imidazol-1-yl)succinic acid], and fast imaging techniques, with spiral acquisition in k-space. We obtained a map of metabolites [136 ms echo time (TE)] and then infused ISUCA in a femoral vein (25 mmol/kg body weight over 110 min) and obtained two consecutive images of pHe within the tumor (40 ms TE, each acquisition taking 25 min). pHe (where ISUCA was present) ranged from 6.5 to 7.5 in voxels of 0.75 microL and did not change detectably when [ISUCA] increased. Infusion of glucose (0.2 mmol/kg.min) decreased tumor pHe by, on average, 0.150 (SE, 0.007; P < 0.0001, 524 voxels in four rats) and increased the mean area of measurable lactate peaks by 54.4 +/- 3.4% (P < 0.0001, 287 voxels). However, voxel-by-voxel analysis showed that, both before and during glucose infusion, the distributions of lactate and extracellular acidity were very different. In tumor voxels where both could be measured, the glucose-induced increase in lactate showed no spatial correlation with the decrease in pHe. We suggest that, although glycolysis is the main source of protons, distributed sites of proton influx and efflux cause pHe to be acidic at sites remote from lactate production.
 ...
PMID:Serial in vivo spectroscopic nuclear magnetic resonance imaging of lactate and extracellular pH in rat gliomas shows redistribution of protons away from sites of glycolysis. 1769 68

Endocytosis and trafficking of receptors and nutrient transporters are dependent on an acidic intra-endosomal pH that is maintained by the vacuolar H(+)-ATPase (V-ATPase) proton pump. V-ATPase activity has also been associated with cancer invasiveness. Here, we report on a new V-ATPase-associated protein, which we identified in insulin-like growth factor I (IGF-I) receptor-transformed cells, and which was separately identified in Caenorhabditis elegans as HRG-1, a member of a family of heme-regulated genes. We found that HRG-1 is present in endosomes but not in lysosomes, and it is trafficked to the plasma membrane upon nutrient withdrawal in mammalian cells. Suppression of HRG-1 with small interfering RNA causes impaired endocytosis of transferrin receptor, decreased cell motility, and decreased viability of HeLa cells. HRG-1 interacts with the c subunit of the V-ATPase and enhances V-ATPase activity in isolated yeast vacuoles. Endosomal acidity and V-ATPase assembly are decreased in cells with suppressed HRG-1, whereas transferrin receptor endocytosis is enhanced in cells that overexpress HRG-1. Cellular uptake of a fluorescent heme analogue is enhanced by HRG-1 in a V-ATPase-dependent manner. Our findings indicate that HRG-1 regulates V-ATPase activity, which is essential for endosomal acidification, heme binding, and receptor trafficking in mammalian cells. Thus, HRG-1 may facilitate tumor growth and cancer progression.
 ...
PMID:Heme-binding protein HRG-1 is induced by insulin-like growth factor I and associates with the vacuolar H+-ATPase to control endosomal pH and receptor trafficking. 1987 48

Manipulation of the extracellular and/or intracellular pH of tumors may have considerable potential in cancer therapy. The extracellular space of most tumors is mildly acidic, owing to exuberant production of lactic acid. Aerobic glycolysis - attributable largely to chronic activation of hypoxia-inducible factor-1 (HIF-1) - as well as tumor hypoxia, are chiefly responsible for this phenomenon. Tumor acidity tends to correlate with cancer aggressiveness; in part, this reflects the ability of HIF-1 to promote invasiveness and angiogenesis. But there is growing evidence that extracellular acidity per se boosts the invasiveness and metastatic capacity of cancer cells; moreover, this acidity renders cancer cells relatively resistant to the high proportion of chemotherapeutic drugs that are mildly basic, and may impede immune rejection of tumors. Thus, practical strategies for raising the extracellular pH of tumors may have therapeutic utility. In rodents, oral administration of sodium bicarbonate can raise the extracellular pH of tumors, an effect associated with inhibition of metastasis and improved responsiveness to certain cytotoxic agents; clinical application of this strategy appears feasible. As an alternative approach, drugs that inhibit proton pumps in cancer cells may alleviate extracellular tumor acidity while lowering the intracellular pH of cancer cells; reduction of intracellular pH slows proliferation and promotes apoptosis in various cancer cell lines. Well-tolerated doses of the proton pump inhibitor esomeprazole have markedly impeded tumor growth and prolonged survival in nude mice implanted with a human melanoma. Finally, it may prove feasible to exploit the aerobic glycolysis of cancers in hyperacidification therapies; intense intracellular acidification of cancer cells achieved by induced hyperglycemia, concurrent administration of proton pump inhibitor drugs, and possibly dinitrophenol, may have the potential to kill cancer cells directly, or to potentiate their responsiveness to adjunctive measures. A similar strategy, but without proton pump inhibition, could be employed to maximize extracellular tumor acidity, enabling tumor-selective release of cytotoxic drugs encased in pH-sensitive nanoparticles.
 ...
PMID:Manipulating tumor acidification as a cancer treatment strategy. 2115 27


1 2 3 4 5 6 Next >>