Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.13.3 (histidine kinase)
 2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temoporfin (meta-tetra (hydroxyphenyl)chlorin; mTHPC) potentiated a 100-fold higher cytotoxic effect than hematoporphyrin derivative (HPD) on two nasopharyngeal carcinoma cell lines (HK1 and CNE2) in terms of the overall photodynamic therapy (PDT) dose. The cellular uptake, evaluated by flow cytometry and spectrophotometry demonstrated that mTHPC exhibited higher uptake ability than HPD. Confocal laser scanning microscopy detection for both the sensitizer and mitochondria probe on the same cell images revealed that both drugs accumulated diffusely in the cytoplasm and that mitochrondria is a target organelle. Photo-activation ruptured the mitochrondria, with more pronounced mitochondrial damage being observed in mTHPC-PDT course. This correlated well with the cell photokilling efficiency of mTHPC.
Cancer Lett 2000 Sep 01
PMID:Cellular uptake, subcellular localization and photodamaging effect of temoporfin (mTHPC) in nasopharyngeal carcinoma cells: comparison with hematoporphyrin derivative. 1093 72

In East Asia and Singapore, the human nasopharyngeal carcinoma (NPC) presented clinically is mainly of the undifferentiated type. In contrast, the well-differentiated squamous NPC is more commonly detected in the West. To study the potential differences in carcinogenesis between undifferentiated and differentiated human NPC, we employed cDNA microarrays to isolate genes that might be specific for human undifferentiated NPC. One of the genes identified to be specifically upregulated in the undifferentiated human NPC cell line CNE-2 is the human imprinting gene H19. Interestingly, H19 is not expressed in the well-differentiated human HK1 NPC cells. Northern blot and in situ hybridization analyses also confirmed that the H19 gene is strongly expressed in the undifferentiated CNE-2 human NPC cell line but not in the well-differentiated HK1 human NPC cell line. In situ hybridization and reverse transcriptase-polymerase chain reaction also demonstrated that H19 is specifically expressed in NPC biopsies and not in non-NPC human tissue biopsies. Furthermore, we demonstrated that deregulation of H19 gene expression in the well-differentiated human HK1 NPC cells could be induced by the hypomethylation of CpG sites of the H19 promoter region. Hypermethylation of gene promoter regions might therefore be an important epigenetic event that plays a role in the differentiation of human NPC cells and the transcriptional silencing of imprinted genes.
Int J Cancer 2003 Mar 20
PMID:Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation. 1256 73

Recent evidence suggests that the machinery of protein synthesis may provide novel targets for anticancer drugs. For example, aberrations in protein synthesis are commonly encountered in established cancers, and disruption by mutation or overexpression of translation factors can cause cellular transformation. We previously demonstrated that the activity of eukaryotic elongation factor 2 (eEF-2) kinase was markedly increased in several forms of malignancy and that nonspecific inhibitors of this enzyme promoted cell death. On the basis of the predicted amino acid sequence of eEF-2 kinase deduced from the cloned cDNA, we hypothesized that inhibitors of prokaryotic histidine kinases might also inhibit the activity of eEF-2 kinase. We describe herein the screening of a series of imidazolium histidine kinase inhibitors and the identification of an active lead compound, NH125. NH125 inhibited eEF-2 kinase activity (IC(50) = 60 nM) in vitro, blocked the phosphorylation of eEF-2 in intact cells, and showed relative selectivity over other protein kinases: protein kinase C (IC(50) = 7.5 microM), protein kinase A (IC(50) = 80 microM), and calmodulin-dependent kinase II (IC(50) > 100 microM). NH125 decreased the viability of 10 cancer cell lines with IC(50)s ranging from 0.7 to 4.7 microM. Forced overexpression of eEF-2 kinase in a glioma cell line produced 10-fold resistance to NH125. In conclusion, these results suggest that identification of potent inhibitors of eEF-2 kinase may lead to the development of new types of anticancer drugs.
Cancer Res 2003 Oct 15
PMID:Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines. 1458 88

Nasopharyngeal carcinoma is a common cancer in South-East Asia, especially among people of Chinese origin. In this report, we investigate the effects of quercetin on the growth of wild-type and mutant p53 nasopharyngeal carcinoma cell lines, HK1 and CNE2 respectively. The wild-type p53 HK1 was more susceptible to growth inhibition by quercetin than the mutant p53 CNE2. The ID50 values for HK1 and CNE2 were 35.0 and 54.5 microM respectively. Cell growth arrest was initiated by the up-regulation of retinoblastoma gene expression, resulting in cell cycle arrest in either the G2/M or G0/G1 phase at 14.8 and 52.1 microM quercetin respectively regardless of the p53 status. Flow cytometry experiments revealed that quercetin-induced apoptosis during the first 24 h followed by necrosis in both HK1 and CNE2. Western blot experiments confirmed that cytotoxic killing of HK1 and CNE2 by quercetin was mediated by the up-regulation of pro-apoptotic protein Bad, caspase-3 and -7, resulting in cell death by apoptosis. Our study demonstrates that quercetin inhibits cell growth of nasopharyngeal carcinoma cell lines HK1 and CNE2 by inhibiting cell cycle progression to S phase. Quercetin is also able to induce apoptosis and necrosis in these cells regardless of the p53 status.
 ...
PMID:Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. 1476 29

Photodynamic therapy (PDT) is a new modality of treatment for cancer. Hypericin is a photosensitizer, which is known to generate reactive oxygen species upon activation with light. We observed that photoactivated hypericin induces the generation of reactive oxygen intermediates in nasopharyngeal cancer (NPC) cells in vitro. There was also significant reduction of Glutathione S-transferase (GST) activity in HK1 and CNE-2 NPC cells and in tumor tissues from the NPC/HK1 murine tumor model by hypericin-mediated PDT. As antioxidants protect cells against phototoxicity, down-regulation of GST activity would potentiate the efficacy of hypericin-PDT treatment.
Cancer Lett 2004 Apr 30
PMID:Photoactivation of hypericin down-regulates glutathione S-transferase activity in nasopharyngeal cancer cells. 1507 26

Histidine kinase inhibitors are being developed as a new class of antimicrobial drugs. We recently demonstrated the activity of a class of histidine kinase inhibitors against a mammalian enzyme, elongation factor-2 kinase (eEF-2K), and the effect of these compounds on cancer cell viability (Arora et al., 2003). To further characterize these compounds, we studied their interaction with ATP-binding cassette transporters, which are known to mediate resistance to a variety of chemotherapeutic agents. The 24 compounds studied belong to three structural series of derivatives of 2-methylimidazolium iodide. We focused this work on a representative compound (NH125) because we found it to be most potent against both histidine kinase and eEF-2K among the series. Cell lines that expressed P-glycoprotein (P-gp) were 2- to 5-fold resistant to NH125. NH125 increased accumulation of P-gp substrates such as paclitaxel and doxorubicin but had no effect on the accumulation of non-P-gp substrates. P-gp modulators verapamil and trans-flupenthixol and MDR1-targeted siRNA increased sensitivity of multidrug-resistant cell lines to NH125. The presence of a benzyl group on the N-3 position of the 2-methylimidazolium iodide was important for the interaction with P-gp. C6-NH, an NH125-resistant cell line, markedly overexpressed P-gp compared with the parental cell line. In animal models, we found that NH125 increased by 129% the survival of sensitive P388 cells bearing mice but had no effect on mice harboring the resistant cell line. These observations indicate that certain histidine kinase inhibitors are substrates for P-gp and hence an important consideration in development of these agents as potential antimicrobial and anticancer agents.
 ...
PMID:P-glycoprotein mediates resistance to histidine kinase inhibitors. 1532 37

Tazarotene-induced gene 1 (TIG1) and Tazarotene-induced gene 3 (TIG3) are retinoid acid (RA) target genes as well as candidate tumor suppressor genes in human cancers. In our study, we have investigated the expression of TIG1 and TIG3 in nasopharyngeal carcinoma (NPC). Loss of TIG1 expression was found in 80% of NPC cell lines and 33% of xenografts, whereas TIG3 was expressed in all NPC samples and immortalized nasopharyngeal epithelial cells. In order to elucidate the epigenetic silencing of TIG1 in NPC, the methylation status of TIG1 promoter was examined by genomic bisulfite sequencing and methylation-specific PCR (MSP). We have detected dense methylation of TIG1 5'CpG island in the 5 TIG1-negative NPC cell lines and xenograft (C666-1, CNE1, CNE2, HONE1 and X666). Partial methylation was observed in 1 NPC cell line HK1 showing dramatic decreased in TIG1 expression. Promoter methylation was absent in 2 TIG1-expressed NPC xenografts and the normal epithelial cells. Restoration of TIG1 expression and unmethylated alleles were observed in NPC cell lines after 5-aza-2'-deoxycytidine treatment. Moreover, the methylated TIG1 sequence was detected in 39 of 43 (90.7%) primary NPC tumors by MSP. In conclusion, our results showed that TIG1 expression is lost in the majority of NPC cell lines and xenografts, while promoter hypermethylation is the major mechanism for TIG1 silencing. Furthermore, the frequent epigenetic inactivation of TIG1 in primary NPC tumors implied that it may play an important role in NPC tumorigenesis.
Int J Cancer 2005 Jan 20
PMID:Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma. 1545 91

Cytokines induce inflammatory and immune responses in tumors after photodynamic therapy (PDT). Since there are no reports of IL-6 in nasopharyngeal cancer (NPC) cells following PDT, we evaluated IL-6 expression in two different NPC tumors after hypericin mediated PDT. Interleukin-6 transcription was significantly upregulated in PDT-treated CNE-2 poorly differentiated cells but not in HK1 well differentiated cells. In vivo, IL-6 mRNA expression was elevated in PDT-treated CNE-2 tumors but not in HK1 tumors. In conclusion, the study elucidated that the cell type, degree of histological differentiation and the basal expression of the cytokine influence the cytokine response following PDT.
Cancer Lett 2006 Apr 28
PMID:Hypericin-mediated photodynamic therapy elicits differential interleukin-6 response in nasopharyngeal cancer. 1593 50

PTEN tumor suppressor gene failure in ras(Ha)-activated skin carcinogenesis was investigated by mating exon 5 floxed-PTEN (Delta5PTEN) mice to HK1.ras mice that expressed a RU486-inducible cre recombinase (K14.creP). PTEN inactivation in K14.cre/PTEN(flx/flx) keratinocytes resulted in epidermal hyperplasia/hyperkeratosis and novel 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas, whereas HK1.ras/K14.cre/PTEN(flx/flx) cohorts displayed a rapid onset of papillomatogenesis due to a synergism of increased AKT activity and extracellular signal-regulated kinase (ERK) elevation. High 5-bromo-4-deoxyuridine labeling in Delta5PTEN papillomas showed that a second promotion mechanism centered on failures in cell cycle control. Elevated cyclin D1 was associated with both HK1.ras/ERK- and Delta5PTEN-mediated AKT signaling, whereas cyclin E2 overexpression seemed dependent on PTEN loss. Spontaneous HK1.ras/Delta5PTEN malignant conversion was rare, whereas TPA promotion resulted in conversion with high frequency. On comparison with all previous HK1.ras carcinomas, such TPA-induced carcinomas expressed atypical retention of keratin K1 and lack of K13, a unique marker profile exhibited by TPA-induced K14.cre/PTEN(flx/flx) papillomas that also lacked endogenous c-ras(Ha) activation. Moreover, in all PTEN-null tumors, levels of ras(Ha)-associated total ERK protein became reduced, whereas phosphorylated ERK and cyclin D1 were lowered in late-stage papillomas returning to elevated levels, alongside increased cyclin E2 expression, in TPA-derived carcinomas. Thus, during early papillomatogenesis, PTEN loss promotes ras(Ha) initiation via elevation of AKT activity and synergistic failures in cyclin regulation. However, in progression, reduced ras(Ha)-associated ERK protein and activity, increased Delta5PTEN-associated cyclin E2 expression, and unique K1/K13 profiles following TPA treatment suggest that PTEN loss, rather than ras(Ha) activation, gives rise to a population of cells with greater malignant potential.
Cancer Res 2006 Feb 01
PMID:PTEN loss promotes rasHa-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via PTEN-associated pathways. 1645 83

Cancer metastasis is a significant contributor to breast cancer patient morbidity and mortality. In order to develop new anti-metastatic therapies, we need to understand the biological and biochemical mechanisms of metastasis. Toward these efforts, we and others have studied metastasis suppressor genes, which halt metastasis in vivo without affecting primary tumor growth. The first metastasis suppressor gene identified was nm23, also known as NDP kinase. Nm23 represents the most widely validated metastasis suppressor gene, based on transfection and knock-out mouse strategies. The biochemical mechanism of metastasis suppression via Nm23 is unknown and likely complex. Two potential mechanisms include binding proteins and a histidine kinase activity. Elevation of Nm23 expression in micrometastatic tumor cells may constitute a translational strategy for the limitation of metastatic colonization in high risk cancer patients. To date, medroxyprogesterone acetate (MPA) has been identified as a candidate compound for clinical testing.
 ...
PMID:Translational approaches using metastasis suppressor genes. 1694 1


<< Previous 1 2 3 4 5 6 7 8 Next >>