Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that integrin-linked kinase (ILK) is upregulated in human HT-144 melanoma cells following TGF-beta1 stimulation. Using mRNA from TGF-beta1 stimulated HT-144 cells and reverse transcriptase polymerase chain reaction, we have isolated a cDNA encoding a protein highly homologous to ILK. Sequencing of the full-length 1359 base pair cDNA and polypeptide translation revealed that this protein, designated ILK-2, differs from the known ILK (hereafter called ILK-1) by only four amino acids, while the cDNA sequence diverges by 102 nucleotides, thus excluding that ILK-2 is an allelic variant of ILK-1. Expression of ILK-2 mRNA was observed in metastatic human HT-144 melanoma and HT-1080 fibrosarcoma cell lines, but not in normal human tissues. Moreover, stimulation of HT-144 cells with TGF-beta1, but not with EGF, PDGF-AB or insulin, induced a selective overexpression of ILK-2 mRNA as compared to ILK-1 mRNA. Bacterially-expressed GST/ILK-2 autophosphorylated and labeled myelin basic protein as well as a recombinant GST/beta3 integrin cytoplasmic tail peptide. Transfection of either ILK-2 or ILK-1 cDNA into the non-metastatic melanoma cell line SK-Mel-2, expressing exclusively ILK-1, induced anchorage independent cell growth and cell proliferation, as demonstrated by growth in soft agar. Our data provide evidence that ILK-2 is a new isoform of ILK-1 that is expressed in some highly invasive tumor cell lines but not in normal adult human tissues and whose expression is regulated by TGF-beta1.
 ...
PMID:Cloning of an isoform of integrin-linked kinase (ILK) that is upregulated in HT-144 melanoma cells following TGF-beta1 stimulation. 1087 59

First line treatment of metastatic melanoma includes the methylating agent dacarbazine or its analogue temozolomide (TMZ) with improved pharmacokinetics and tolerability. However, the prognosis of the metastatic disease is poor and several trials are evaluating TMZ in polychemotherapy protocols. The novel glutathione transferase P1-1 (GSTP1-1) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has recently shown activity against melanoma through c-Jun N-terminal kinase activation. In this study we have investigated the in vitro and in vivo efficacy of NBDHEX and TMZ combination against melanoma. The results indicated that NBDHEX and TMZ exerted in vitro synergistic anti-proliferative effects in murine B16 and human A375 melanoma cells. In B16 cells TMZ as single agent caused cell accumulation at the G(2)/M phase of cell cycle, whereas NBDHEX induced mainly apoptotic effects. NBDHEX provoked a higher level of p53 phosphorylation with respect to TMZ and the drug combination caused a more than additive increase of p53 activation. The in vivo efficacy of NBDHEX and TMZ has been investigated in an orthotopic B16 model. Treatment with NBDHEX provoked a reduction of tumour growth comparable to that obtained with TMZ, whereas the drug combination significantly increased tumour growth inhibition with respect to the single agents, without worsening TMZ myelotoxicity. Immunohistochemical analysis of tumour grafts revealed a profound reduction of Cyclin D1 and CD31 in all treatment groups; VEGF expression was, instead, markedly decreased only in NBDHEX or NBDHEX and TMZ treated samples. These findings indicate that NBDHEX represents a good candidate for combination therapies including TMZ, offering new perspectives for the treatment of melanoma.
 ...
PMID:The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma. 2126 21

P-170 glycoprotein, glutathione and glutathione S-transferases are important in in vitro drug resistance, but their clinical relevance is unclear. Therefore glutathione content, glutathione S-transferase enzyme activity, isoenzyme composition as well as P-170 glycoprotein level were studied in metastases of malignant melanomas of thirteen patients. P-170 glycoprotein and glutathione S-transferases were quantified by immunoblotting with monoclonal antibodies, glutathione S-transferase enzyme activity was measured with 1-chloro-2,4-dinitrobenzene as substrate, and glutathione was assayed by HPLC. Glutathione and glutathione S-transferase enzyme activity were measurable in all samples and mean values were 40+/-7 nmol/mg protein (mean+/-SEM; range: 13-98) and 310+/-72 nmol/min mg protein (range: 15-819), respectively. Glutathione S-transferases present were mainly of class pi (2817+/-402 ng/mg protein); class alpha enzymes were detectable only in one case in low amounts (71 ng/mg protein), and class mu transferases were present in 5 out of the 13 samples (38%; 391+/-206 ng/mg protein). The P-170 glycoprotein plasma membrane located drug efflux pump was found in 8 out of 12 samples (67%). In three samples values were much higher as compared to the other specimens. In the metastatic melanoma of one patient, both high levels of glutathione S-transferase and P-170 glycoprotein were found. Further studies are necessary to reveal whether melanoma tissues containing high levels of P-170 glycoprotein, glutathione S-transferases or a combination of both systems do respond differently towards anti-cancer drug treatment.
 ...
PMID:Glutathione, glutathione-s-transferase and p-170 glycoprotein in metastases of malignant melanomas. 2156 56