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

We report the synthesis of novel acid-responsive therapeutic nanoparticles (NPs) with sub-100 nm size consisting of polymer--cisplatin conjugates. The uniqueness of these drug delivery polymeric NPs lies in the covalent conjugation of each cisplatin drug to the hydrophobic segment of two biocompatible diblock copolymer chains through a hydrazone bond, resulting in highly differential drug release profile at different environmental acidity. We demonstrate that the synthesized polymer--cisplatin conjugates can readily precipitate to form sub-100 nm NPs in aqueous solution due to their very low critical micelle concentration (CMC). The resulting NPs show well-controlled cisplatin loading yield, excellent acid-responsive drug release kinetics, and enhanced in vitro cytotoxicity against ovarian cancer cells as compared to free cisplatin. As an environmentally sensitive drug delivery vehicle, these NPs can potentially minimize the drug loss during NP circulation in the blood, where the pH value is neutral, and trigger rapid intracellular drug release after the NPs are endocytosed by the target cells. This characteristic drug release profile holds the promise to suppress cancer cell chemoresistance by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload.
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PMID:Polymer--cisplatin conjugate nanoparticles for acid-responsive drug delivery. 2003 97

Caged proteins have been utilized as a biological container in a wide range of applications from material science to biomedicine, and GALA peptide has been known to undergo coil-to-helix transition upon the increased acidity. In this study, GALA synthetic peptide is incorporated to cage protein by genetic modification. Our engineered caged scaffold retains intact at the physiological pH but dissociate completely at pH 6.0, and the dissociated subunits are re-assembled simply by neutralization to biological pH. This acid-induced dissociation has the potential as molecular switch in vivo as well as in vitro so that the acid-sensitive caged proteins are applicable to drug delivery system for acidic target sites such as tumor. Since our design depends on the conformational transition of GALA peptide, not on removal of characteristic interface observed only in viral capsid-like protein, non-viral caged proteins can also be engineered to have molecular switching function. Therefore, this design for acid-sensitive scaffold would broaden the width of applications in nanotechnology including biomimetic material synthesis and biomedicine.
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PMID:The incorporation of GALA peptide into a protein cage for an acid-inducible molecular switch. 2035 42

Vacuolar H+-ATPases function in bone resorption, pH homeostasis and tumor metastasis, play an important role in regulating the extra- and intracellular pH (pHe and pHi) in various eukaryotic cells. Acidity is one of the main features of the tumors. The Vacuolar H+-ATPases are the primary responsible for the control of tumor microenvironment by proton extrusion to the extracellular medium, which play a crucial role in tumor invasion, metastasis and chemoresistance. Therefore our study aimed to uncover the relationship between Vacuolar H+-ATPases and the pHi value. Three adenocarcinoma cell lines of digestive system including SGC7901, HT29 and PATU8988 were cultured in RPMI-1640 supplemented with 10% fetal bovine serum and antibiotics. BCECF-AM pH-sensitive fluorescent probe was used to measure the pHi value of cells. Western blot and immunofluorescent staining were respectively applied to determine the protein expression and intracellular distribution of Vacuolar H+-ATPases. The pHi value of HT29 was the highest, whereas the pHi value of PATU8988 was the lowest and of SGC7901 was in the midst according to fluorescent intensity of BCECF. Similar results were obtained in the protein expression and the IOD (integral optical density) of Vacuolar H+-ATPases in them. The pHi value indirectly represented by fluorescent intensity of BCECF was positively correlated with protein expression of Vacuolar H+-ATPases in an exponential manner.
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PMID:Expression of Vacuolar H+-ATPases and the intracellular pH values in three adenocarcinoma cell lines of digestive system. 2038 78

Nitrite has been implicated in carcinogenesis, especially under acidic conditions such as in the stomach or in urine, where it forms nitrosating species that can react with secondary amines to form nitrosamines. Recent studies have shown that nitrite and acid form a variety of other nitrogen oxides in vivo including nitric oxide-a compound with documented antitumor activity. Here we tested the effects of nitrite on bladder tumor cells incubated in mildly acidified urine. Nitrite (50 microM) inhibited thymidine incorporation in human T24 bladder cancer cells. This inhibition required slight acidification (pH 5.5-6), and no effect of nitrite could be observed at pH 7. Nitrite effects were further augmented in the presence of ascorbic acid, whereas ascorbic acid alone had no effect. The effects were paralleled by formation of nitric oxide gas. We here demonstrate an inhibitory effect of nitrite on cancer cell replication at concentrations and acidity commonly found in urine and gastric juice. The inhibitory effect is likely caused by nitric oxide and possibly other reactive nitrogen oxides formed from acidified nitrite.
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PMID:Inhibition of cancer cell replication by inorganic nitrite. 2043 71

Carbonic anhydrase (CA) XII, an extracellular enzyme involved in the regulation of the microenvironment acidity and tumor malignant phenotype, was originally identified as a protein overexpressed in some types of cancers, including breast cancer. However, the cellular function and mechanism of CAXII remained unclear. In this study, the effects of CAXII expression on invasion and migration of breast cancer cells was investigated. Gene knockdown of CAXII in the human breast cancer cell line MDA-MB-231 resulted in decreased invasion and migration by interfering with the p38 MAPK pathway. CAXII knockdown also decreased the expression of matrix metalloproteinase (MMP)-2, MMP-9, and urokinase-type plasminogen activator (u-PA), but increased tissue inhibitor of metalloproteinases (TIMP)-2 and plasminogen activator inhibitor (PAI)-1 expression. Furthermore, decreased invasive and migration ability of CAXII-knockdown cells were restored by an overexpression of CAXII. Results also showed that CAXII knockdown may decrease anchorage-independent growth and cell growth by inhibiting CDK6 and cyclin D1 expression. Furthermore, the impact of CAXII knockdown on invasion, migration and cell growth was further evidenced by effects on tumor size and metastasis of MDA-MB-231 cells in vivo. Taken together, these data suggested that CAXII may affect the capability of invasion and migration of MDA-MB-231 cells, which may be mediated through the p38 MAPK pathway.
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PMID:Carbonic anhydrase XII promotes invasion and migration ability of MDA-MB-231 breast cancer cells through the p38 MAPK signaling pathway. 2043 30

The vacuolar ATPases are ATP-dependent proton pumps whose functions include the acidification of intracellular compartments and the extrusion of protons through the cell cytoplasmic membrane. These pumps play a pivotal role in the regulation of cell pH in normal cells and, to a much greater extent, in tumor cells. In fact, the glucose metabolism in hypoxic conditions by the neoplasms leads to an intercellular pH drift towards acidity. The acid microenvironment is modulated through the over-expression of H+ transporters that are also involved in tumor progression, invasiveness, distant spread and chemoresistance. Several strategies to block/downmodulate the efficiency of these transporters are currently being investigated. Among them, proton pump inhibitors have shown to successfully block the H+ transporters in vitro and in vivo, leading to apoptotic death. Furthermore, their action seems to synergize with conventional chemotherapy protocols, leading to chemosensitization and reversal of chemoresistance. Aim of this article is to critically revise the current knowledge of this cellular machinery and to summarize the therapeutic strategies developed to counter this mechanism.
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PMID:Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. 2045 83

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.
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PMID:Manipulating tumor acidification as a cancer treatment strategy. 2115 27

This review presents the state of the art of pH-responsive polymeric micelles for cancer drug delivery. Solid tumors have a weakly acidic extracellular pH (pH < 7), and cancer cells have even more acidic pH in endosomes and lysosomes (pH 4-6). The pH-gradients in tumor can be explored for tumor targeting and drug release in cancer drug delivery by applying pH-responsive polymeric micelles. The pH-responsive polymeric micelles consist of a corona and a core, and are made of amphiphilic copolymers, in which there are pH-responsive polymeric blocks. Two types of pH-responsive polymers-protonizable polymers and acid-labile polymers have been mainly used to make pH-responsive micelles for drug delivery. The protonizable polymers are polybases or polyacids, and their water-soluble/insoluble or charge states undergo changes with the protonation or deprotonation stimulated by external acidity, while the acid-labile polymers change their physical properties by chemical reaction stimulated by the acidity. Polymeric micelles whose core or coronas respond to the tumor extracellular acidity can be explored for triggering the fast release of the carried drug, activating the targeting group and accelerating the endocytosis of drug-loaded polymeric micelles, and those whose core or coronas respond to the tumor lysosomal acidity can be used for facilitating their escape from the lysosomes and targeting the nucleus. Various in vivo and in vitro experiments demonstrated that pH-responsive polymeric micelles are effective for cellular targeting, internalization, fast drug release and nuclear localization, and hence enhancing the therapeutic efficacy and reducing the side effect of cancer chemical therapy.
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PMID:[Advances in the study of tumor pH-responsive polymeric micelles for cancer drug targeting delivery]. 2135 64

Metastasis is a multistep process that culminates in the spread of cells from a primary tumor to a distant site or organs. For tumor cells to be able to metastasize, they have to locally invade through basement membrane into the lymphatic and the blood vasculatures. Eventually they extravasate from the blood and colonize in the secondary organ. This process involves multiple interactions between the tumor cells and their microenvironments. The microenvironment surrounding tumors has a significant impact on tumor development and progression. A key factor in the microenvironment is an acidic pH. The extracellular pH of solid tumors is more acidic in comparison to normal tissue as a consequence of high glycolysis and poor perfusion. It plays an important role in almost all steps of metastasis. The past decades have seen development of technologies to non-invasively measure intra- and/or extracellular pH. Most successful measurements are MR-based, and sensitivity and accuracy have dramatically improved. Quantitatively imaging the distribution of acidity helps us understand the role of the tumor microenvironment in cancer progression. The present review discusses different MR methods in measuring tumor pH along with emphasizing the importance of extracelluar tumor low pH on different steps of metastasis; more specifically focusing on epithelial-to-mesenchymal transition (EMT), and anti cancer immunity.
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PMID:Imaging pH and metastasis. 2138 39

Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.
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PMID:The spatial organization of proton and lactate transport in a rat brain tumor. 2139 Mar 24


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