Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Around 200-600 million Asians chew areca (also called betel), which contains a mixture of areca nut and other ingredients. Epidemiological evidences indicated that areca use is tightly linked to oral carcinogenesis. This study investigated the effects of ripe areca nut extract (ANE) on cultured normal human oral keratinocyte (NHOK). Acute subtoxic ANE treatment inhibited DNA synthesis and induced cell cycle arrest at G1 phase in early passage (< 4th passage) cells. This was accompanied by a slight increase in the sub-G1 cellular fraction. O6-Methylguanine-DNA methyltransferase (MGMT), Hsp27 and p38MAPK was upregulated. p16 and p21 were remarkably upregulated early and declined afterwards. In contrast, the increase of dephosphorylated Rb seemed to be secondary to the episodes of p16 and p21 upregulation. To simulate the chronic areca exposure in vivo, constant ANE treatment in serial NHOK culture was performed. It resulted in a significant decrease in the population doubling, increase in senescence-associated beta-galactosidase (SA-beta-Gal) and decrease in cell proliferation in NHOK of late passages (> or = 4th passage). Induction of senescence-associated phenotypes, G2/M accumulation and genomic instability following long-term ANE treatment were also observed in a low-grade oral carcinoma cell. ANE-treated NHOK also had a higher nuclear factor-kappaB (NF-kappaB) fraction and a lower cytosolic IkappaBalpha level relative to the control in late passages. Moreover, electrophoretic mobility shift assay (EMSA) indicated that ANE treatment shifted the NF-kappaB complex from high mobility position to lower mobility position in late-passaged NHOK. ANE treatment also upregulated IL-6 and cyclooxygenase-2 (COX-2) mRNA expressions in late-passaged NHOK. In summary, our findings suggest that ANE induces the cell cycle arrest at G1/S phase and the occurrence of senescence-associated phenotypes of NHOK. The upregulation of p38MAPK, p16, p21, NF-kappaB, IL-6 and COX-2 are likely to participate in the control of these impacts.
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PMID:Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte. 1647 77

Replicative senescence limits the proliferation of somatic cells passaged in culture and may reflect cellular aging in vivo. The most widely used biomarker for senescent and aging cells is senescence-associated beta-galactosidase (SA-beta-gal), which is defined as beta-galactosidase activity detectable at pH 6.0 in senescent cells, but the origin of SA-beta-gal and its cellular roles in senescence are not known. We demonstrate here that SA-beta-gal activity is expressed from GLB1, the gene encoding lysosomal beta-D-galactosidase, the activity of which is typically measured at acidic pH 4.5. Fibroblasts from patients with autosomal recessive G(M1)-gangliosidosis, which have defective lysosomal beta-galactosidase, did not express SA-beta-gal at late passages even though they underwent replicative senescence. In addition, late passage normal fibroblasts expressing small-hairpin interfering RNA that depleted GLB1 mRNA underwent senescence but failed to express SA-beta-gal. GLB1 mRNA depletion also prevented expression of SA-beta-gal activity in HeLa cervical carcinoma cells induced to enter a senescent state by repression of their endogenous human papillomavirus E7 oncogene. SA-beta-gal induction during senescence was due at least in part to increased expression of the lysosomal beta-galactosidase protein. These results also indicate that SA-beta-gal is not required for senescence.
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PMID:Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. 1662 97

We previously reported that methoxyamine (an inhibitor of base excision repair) potentiates iododeoxyuridine (IUdR)-induced radiosensitization in human tumor cells. In this study, we investigated the potential mechanisms of this enhanced cell death. Human colorectal carcinoma RKO cells were exposed to IUdR (3 micromol/L) and/or methoxyamine (3 mmol/L) for 48 hours before ionizing radiation (5 Gy). We found that IUdR/methoxyamine altered cell cycle kinetics and led to an increased G1 population but a decreased S population before ionizing radiation. Immediately following ionizing radiation (up to 6 hours), IUdR/methoxyamine-pretreated cells showed a stringent G1-S checkpoint but an insufficient G2-M checkpoint, whereas a prolonged G1 arrest, containing 2CG1 and 4CG1 cells, was found at later times up to 72 hours. Levels of cell cycle-specific markers [p21, p27, cyclin A, cyclin B1, and pcdc2(Y15)] and DNA damage signaling proteins [gammaH2AX, pChk1(S317), and pChk2(T68)] supported these altered cell cycle kinetics. Interestingly, we found that IUdR/methoxyamine pretreatment reduced ionizing radiation-induced apoptosis. Additionally, the extent of cell death through necrosis or autophagy seemed similar in all (IUdR +/- methoxyamine + ionizing radiation) treatment groups. However, a larger population of senescence-activated beta-galactosidase-positive cells was seen in IUdR/methoxyamine/ionizing radiation-treated cells, which was correlated with the increased activation of the senescence factors p53 and pRb. These data indicate that IUdR/methoxyamine pretreatment enhanced the effects of ionizing radiation by causing a prolonged G1 cell cycle arrest and by promoting stress-induced premature senescence. Thus, senescence, a novel ionizing radiation-induced tumor suppression pathway, may be effectively targeted by IUdR/methoxyamine pretreatment, resulting in an improved therapeutic gain for ionizing radiation.
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PMID:Methoxyamine potentiates iododeoxyuridine-induced radiosensitization by altering cell cycle kinetics and enhancing senescence. 1664 59

Blockade of CTLA-4 by monoclonal antibodies (mAb) can mediate regression of tumors and increase the efficacy of tumor antigen specific vaccines. Blockade of CTLA-4 has also been shown to significantly increase the avidity of antigen-specific T cells after immunization with live recombinant viral vector based vaccine. Here, we demonstrate a biological synergy between CTLA-4 blockade and active vaccine therapy consisting of recombinant vaccinia and avipox viruses expressing carcinoembryonic antigen (CEA) and three T cell costimulatory molecules to enhance antitumor effects. However, this synergy was very much dependent on the temporal relationship of scheduling of the two agents. We evaluated the strategies in both a foreign antigen model using beta-galactosidase as immunogen, and in a "self" antigen model using CEA as immunogen. For antitumor activity the model used consisted of mice transgenic for human CEA and a murine carcinoma cell line transfected with CEA. The enhanced antitumor activity after vaccine and CTLA-4 blockade did not result in any signs of autoimmunity. These studies form a rational basis for the use of vector-based vaccines with anti-CTLA-4 and demonstrate that both enhancement of positive costimulatory signals and inhibition of negative costimulatory signals can be simultaneously exploited. These studies also underscore the importance of "drug" scheduling in vaccine combination therapies.
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PMID:The combined activation of positive costimulatory signals with modulation of a negative costimulatory signal for the enhancement of vaccine-mediated T-cell responses. 1731 54

Recently, suicide gene therapy using the herpes simplex virus thymidine kinase (HSVtk) gene followed by ganciclovir (GCV) administration was evaluated for the treatment of cancer. The purpose of this study was to investigate the effectiveness of suicide gene therapy using the replication-deficient recombinant adenovirus vector for human oral squamous carcinoma cell lines. To evaluate transduction efficiency, each cell line was transduced in vitro with an adenovirus vector containing the beta-galactosidase gene. By 24 hours after transduction, nearly 100% of the cells were transduced at a multiplicity of infection (MOI) of 10, and from 30 to 10% at an MOI of 1. Next, each cell line was transduced with an adenovirus vector containing the HSVtk gene, and a subsequent administration of GCV for the assessment of suicide gene therapy. A subsequent administration of GCV resulted in complete tumor cell death. In addition, we conducted a morphological analysis of that cell death using video-enhanced contrast differential interference contrast microscopy, and we observed that it included both apoptosis and necrosis after HSVtk gene and GCV treatment. These results suggest that adenovirus-mediated suicide gene therapy induced remarkable cytotoxicity with a bystander effect in human oral squamous cell carcinoma thus suggesting an effective treatment strategy for that tumor.
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PMID:Suicide gene therapy using adenovirus vector for human oral squamous carcinoma cell line in vitro. 1737 74

PEDF is one of the most potent inhibitor of angiogenesis. Loss of PEDF was found in human prostate tumors and associated with the progression toward a metastatic phenotype. To test the therapeutic potential of PEDF, we constructed a replication-defective adenoviral vector capable of efficient transduction and expression of PEDF (Ad-PEDF) in PC-3 prostate carcinoma cells. As controls, we used adenoviruses expressing beta-galactosidase (Ad-LacZ). We showed that overexpression of PEDF inhibited proliferation of cells and augmented apoptosis in serum-starved cells, in comparison with Ad-LacZ. Furthermore, Ad-PEDF suppresses anchorage-independent growth cells in soft agar and tumor formation in athymic nude mice associated with decreased microvessel density. Microarray analysis showed that 56 out of 8464 genes were found to be upregulated and downregulated in the PC-3 infected with Ad-PEDF as compared with Ad-LacZ. The differentially expressed genes cover a broad range of functional activities including catalytic activity, protein binding, signal transduction activity and cell invasion. Among them, PAI-2 and DRHC were confirmed to be upregulated with real-time PCR and Western blot, suggesting a possible association with PEDF-induced signaling for cell motility and metastasis. These results can contribute to our understanding of the molecular mechanisms of treatment strategies of PEDF for prostate cancer.
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PMID:Adenovirus-mediated PEDF expression inhibits prostate cancer cell growth and results in augmented expression of PAI-2. 1747 Oct 21

A polysaccharide-rich substance isolated from black currant, named cassis polysaccharide (CAPS), was partially digested with beta-galactosidase from Aspergillus oryzae and its immunostimulatory activity was investigated. The in vitro cytokine-inducing effect of CAPS on RAW264 cells was gradually decreased along with lowering of the average MW of CAPS. In vivo, partially digested CAPS with a mean MW of approximately 20,000 showed the most potent antitumor activity against Ehrlich carcinoma in mice.
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PMID:Improvement of the antitumor activity of black currant polysaccharide by an enzymatic treatment. 1748 44

Inactivation of tumor suppressor p53 accompanies the majority of malignant diseases in humans. Restoration of p53 functions in tumor results in death of cancer cells, which can be used in cancer therapy. In cervical cancer a product of E6 gene of the human papilloma virus promotes accelerated degradation of p53 in proteasome system. Therefore, one of the approaches to reactivation of p53 in cervical carcinoma cells could be the use of small molecules that inhibit functions of viral proteins. By using as a test system human cervical carcinoma cells (HeLa cell line bearing human papilloma virus type 18, HPV-18) with introduced reporter construct that expresses beta-galactosidase under control of a p53-dependent promoter we carried out screening of a library of small molecules to select small molecules capable of reactivating transcriptional activity of p53. We then characterized the effects of two most active compounds in cell lines that differ in the status of p53-dependent signaling pathway. Both of the compounds caused specific activation of p53 in the cell lines expressing HPV-18, to a lesser extent--HPV-16, and do not cause any effect in control p53 negative cells, or in the cells with undisrupted p53 pathway. Activation of p53 in cervical carcinoma cells was accompanied by the induction of the p53-dependent gene CDKN1 (p21), by inhibition of proliferation, and by the induction of apoptosis. Both of the compounds were capable of deep inhibition of transcription from the HPV genome, which apparently was the cause for p53 reactivation in response to decreased expression of the E6 protein. The observed low toxicity for normal cells allows considering these chemical compounds as prototypes for future anticancer drugs.
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PMID:[Transcriptional inhibition of human papilloma virus in cervical carcinoma cells reactivates functions of the tumor suppressor p53]. 1768 29

The improvement of the transfection efficiency of the non-viral-based gene delivery systems is a key issue for the application in gene therapy. We have previously described an archaeal histone-like protein-based (HPhA) gene delivery system and showed that HPhA formed stable non-covalent complexes with nucleic acids and improved their delivery by using beta-galactosidase as a reporter gene. In this study, the wild-type p53 gene was transfected into the cancer cells using the HPhA as a vector, and the expression level and the activity of p53 gene were evaluated both in vitro and in vivo. Gene expression was determined by real-time reverse transcriptase-PCR and western blotting analysis. The cellular growth inhibition and apoptosis of HPhA-mediated p53 transfection were assessed by XTT (sodium 3'-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate) assay and annexin V-FITC (fluorescein isothiocyanate) staining, respectively. Further more, transfection of HPhA/p53 into CNE (nasopharyngeal carcinoma cell line)-xenografted nude mice was performed and tumor growth was measured. The present study demonstrates that HPhA enhances the efficiency of p53 gene transfer and antitumor activity compared with the widely used Lipofectamine. These results demonstrate that HPhA enhances the in vitro and in vivo efficiency of p53 gene transfer and suggest that it may be served as a promising tool for gene delivery and gene therapy.
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PMID:An archaeal histone-like protein mediates efficient p53 gene transfer and facilitates its anti-cancer effect in vitro and in vivo. 1785 24

Anthracycline antibiotics, particularly doxorubicin (DOX) and daunorubicin, have been used extensively in the treatment of human malignancies. However, cardiotoxicity and multidrug resistance are significant problems that limit the clinical efficacy of such agents. Rational design to avoid these side effects includes strategies such as drug targeting and prodrug synthesis. The DOX prodrug N-(beta-D-glucopyranosylbenzyloxycarbonyl)-doxorubicin (prodrug 1) was synthesized for specific activation by beta-galactosidase, which is expected to release in necrotic areas of tumor lesions. Described here is the safety, pharmacokinetics, and biodistribution studies of a beta-galactoside prodrug of DOX. In vivo safety evaluation was done in the Ehrlich Ascites Carcinoma (EAC) tumor model. The dose of DOX was 8 mg/kg and the dose of prodrug was 8 mg/kg and 24 mg/kg of DOX equivalents. Our results on cytotoxicity, which demonstrated compression in the number of EAC cells and their viability, substantiate these data. Prodrug 1 was safe up to a dose of 24 mg/kg of DOX equivalents in EAC mice. The pharmacokinetics and biodistribution of prodrug (300 mg/kg) in normal mice were determined and compared with DOX (20 mg/kg). Administration of DOX in normal mice resulted in a peak plasma concentration of 19.45 microM (t = 30 minutes). Prodrug injection resulted in 3- to 16-fold lower concentrations in the tissues of normal mice. As it is more polar, lower levels were observed in tissues and plasma in contrast to the parent compound DOX. In vivo safety studies have shown that prodrug 1 had a maximum tolerated dose compared with DOX and led to improved pharmacokinetics in normal mice.
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PMID:Safety, pharmacokinetics and biodistribution studies of a beta-galactoside prodrug of doxorubicin for improvement of tumor selective chemotherapy. 1860 62


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