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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of apoptosis induced by 1-(beta-D-arabinofuranosyl)cytosine (AraC) with protein kinase inhibitors (i.e. staurosporine, CGP 41251-a protein kinase C (PKC)-selective staurosporine derivative and protein tyrosine kinase (PKT) inhibitor genistein) was examined in two human multidrug-resistant promyelocytic leukemia (HL-60) cell lines with different cell membrane drug resistance-associated glycoproteins (i.e. HL-60/VCR:MDR1 gene coded Pgp/p170 and HL-60/ADR: MRP gene coded non-Pgp/p190). Staurosporine stimulated AraC-induced apoptosis in the parental drug-sensitive HL-60 cells and both examined multidrug resistant HL-60 sublines. The stimulation of AraC-induced apoptosis by PKC selective inhibitor CGP 412251 and PTK-inhibitor genistein was approximately equal to that of staurosporine in HL-60/ADR cell line. In both parental drug sensitive HL-60 cells and Pgp/p170 positive (MDR1) HL-60/VCR, staurosporine-stimulated AraC-induced apoptosis was higher than that stimulated by the PKC selective CGP 41251 inhibitor, or PTK-inhibitor genistein. These data suggest that the molecular pathway(s) for AraC-induced apoptosis can be activated and stimulated by PKC- and PTK-inhibitors in both examined drug-resistant HL-60 cell lines. Furthermore, these data suggest that although both PKC- and PTK-dependent mechanisms are involved in AraC-induced apoptosis, in the drug-sensitive HL-60 cells and multidrug-resistant HL-60/VCR (Pgp/p170) cells this process is mediated at least partially, also by PKC- and PTK-independent mechanisms, activated by staurosporine.
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PMID:Stimulation of 1-(beta-D-arabinofuranosyl)cytosine (AraC)-induced apoptosis in the multidrug resistant human promyelocytic leukemia cell lines with protein kinase inhibitors. 899 46

Morphologic (Shimada classification--SC, original and modified histologic grades--OHG and MHG) and nonmorphologic (serum LDH, 1 p del, DNA index, N-myc copy number, telomerase activity, and expression of MRP, MDR1, and TRK) prognostic markers for NB have been reviewed. The functional role of these nonmorphologic markers in the development and progression of this disease include abnormal cell proliferation, resistance to chemotherapeutic agents, and induction of apoptosis. A statistically significant association between high OHG/MHG (grade 3), DNA index of 1 (diploidy), > 1 copy of N-myc per haploid genome and serum LDH of > or = 1500 IU/1 (p < 0.001 for each) has been described. In SC, undifferentiated histology and high MKI are associated with N-myc amplification. However, a lack of correlation between morphology and N-myc amplification has been found in localized NB. Confirmation of these observations must now be obtained on larger numbers of prospectively studied cases. Data on correlation for various prognostic markers could provide guidelines for identification of subsets of NB having strongly significant, readily determinable, reproducible, and relatively inexpensive prognostic markers that could ultimately be used to design an algorithm for risk-specific therapy.
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PMID:Correlation between morphologic and nonmorphologic prognostic markers of neuroblastoma. 938 56

We previously showed that combined neoadjuvant doxorubicin (DOX) treatment and orthotopic liver transplantation produced a 3-year tumor-free survival rate of 54% in stage II-IVa nonresectable hepatocellular carcinomas (HCCs). These patients received posttransplant immunosuppressive doses of cyclosporin A (CsA). CsA has been shown to modify the function of a membrane P-glycoprotein (Pgp) whose overexpression is associated with a multidrug-resistant (MDR1) phenotype. This study utilized HCC cell lines to characterize the in vitro chemomodulatory properties of CsA as found in posttransplant patient plasma to consider the hypothesis that CsA may prolong posttransplant survival by enhancing the therapeutic efficacy of DOX against multidrug-resistant hepatoma cells. We characterized Pgp expression in the HCC lines Hep3B, Hep G2, and SK-HEP-1 by immunohistochemistry and the reverse transcription-polymerase chain reaction. The combined cytotoxicity of DOX + CsA was examined by [3H]thymidine uptake and flow cytometric drug-retention assays. Pgp expression was assessed further after prolonged (10-day) treatment with CsA. Hep3B and Hep G2 cells expressed low to moderate levels of Pgp. The effective DOX dose required for inhibiting MDR1(+) Hep3B and Hep G2 cell proliferation by 50% (DOX IC50) was 44.5 ng/ml and 43.5 microgram/ml, as compared with 10.7 ng/ml for Pgp-negative SK-HEP-1 cells. Optimal concentrations of CsA (0.8 micrometer) lowered DOX IC50 for Hep3B cells and Hep G2 cells by 6-fold and 4-fold, respectively. Similarly, plasma from patients containing immunosuppressive levels of CsA lowered DOX IC50 of the MDR1(+) Hep G2 cells by up to 4-fold. Prolonged exposure to CsA did not affect its chemosensitizing capacity or Pgp expression of HCC cells. PSC-833, a nonimmunosuppressive analogue of CsA, was equally effective in reducing the DOX IC50 of MDR1(+) HCC cells. CsA and PSC-833 increased drug retention by approximately 75%, but did not significantly affect hepatoma cell viability or Pgp expression. Pharmacological concentrations of cyclosporin analogues, including one nonimmunosuppressive form, enhance DOX cytotoxicity of MDR1(+) HCC cells by modulating drug retention. CsA as found in posttransplant patient plasma enhanced DOX cytotoxicity to human MDR1(+) hepatoma cells in vitro, albeit at less than optimal chemosensitizing concentrations. Prolonged exposure to CsA did not affect its chemosensitizing properties or block Pgp expression of HCC cells. These findings support our hypothesis that in vivo immunosuppressive levels of CsA may enhance DOX chemotherapeutic efficacy on MDR1(+) HCC cells.
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PMID:Chemosensitization of human hepatocellular carcinoma cells with cyclosporin A in post-liver transplant patient plasma. 981

The MDR1 gene encoding the multidrug pump P-glycoprotein is transcriptionally activated in response to diverse extracellular stimuli, including the tumor promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the signal transduction pathway responsible is unknown. Downstream of protein kinase C (PKC), the effects of TPA are often mediated by the Raf-1/MEK/ERK mitogen-activated protein kinase (MAPK) cascade, and Raf-1 has been implicated in MDR1 induction by serum and mitogens. Therefore, we examined the potential role of MAPK activation in TPA-mediated MDR1 induction in human leukemia K562 cells. MDR1 mRNA expression was significantly increased by TPA in the concentration range of 4 - 100 nM, with a maximal response 5 - 10 h after TPA addition. TPA-mediated MDR1 induction was inhibited by several PKC inhibitors including staurosporine, H7 and calphostin C. TPA stimulated the subcellular translocation of PKCalpha from the cytosol to the membrane and nucleus but did not affect other PKC isozymes. TPA also activated the Raf1/MEK/ERK cascade and activated another MAPK member, p38, but not JNK. In order to determine the potential role of MAPKs in MDR1 induction by TPA, specific inhibitors were utilized. The MEK inhibitor PD 098059, as well as the PKC inhibitors, completely blocked TPA-mediated ERK activation. However, under identical conditions, MDR1 induction by TPA was completely unaffected by PD 098059. Furthermore, SB 202190, which effectively inhibited TPA-mediated p38 activation, failed to inhibit TPA-induced MDR1 mRNA expression. These data demonstrate that MDR1 induction by TPA occurs via a PKC-dependent mechanism that operates independently of ERK, p38 or JNK pathways, and thus have important implications for understanding the mechanisms of MDR1 induction by extracellular stimuli.
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PMID:Phorbol ester induced MDR1 expression in K562 cells occurs independently of mitogen-activated protein kinase signaling pathways. 1052 56

Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro. The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-pi, metallothionein, O6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).
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PMID:Protein expression profiles indicative for drug resistance of non-small cell lung cancer. 1217 90

Homoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor cell growth at molar ranges comparable to established cytostatic drugs, whereas CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50) values of CET and HHT were significantly correlated to doxorubicin, vincristine, methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA). We tested both drugs for resistance of cell lines which selectively overexpress the multidrug resistance (MDR)-conferring genes P-glycoprotein/ MDR1 (CEM/ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines did not show cross-resistance compared to their drug-sensitive counterparts. As the tumor suppressor p53 is another important factor of chemoresistance, we also analyzed the possibility that p53 affects the response of tumor cells to CET and HHT. Comparing the p53 mutational status of the 55 NCI cell lines (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation. Thus, CET and HHT were more active in cell lines without p53 mutation. We correlated the IC50 values of CET and HHT with the cell doubling times of the 55 NCI cell lines as proliferation parameter and observed that rapidly growing cells were more susceptible than slowly growing cell lines. We conducted a search mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines and correlated the data with the IC50 values for CET and HHT. Of these genes 61 (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50 values for HHT indicating the multifactorial mode of action of these drugs in cancer cells. We have chosen one example from these genes to test a causative role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal growth factor receptor ( EGFR) gene truncated in its extracellular domain through a deletion of exons 2-7 (Delta EGFR) were 14-fold more resistant to HHT than control cells transfected with mock expression vector or non-transfected cells. The present investigation presents a starting point to dissect the genes and molecular pathways involved in the tumor cells' response to CET and HHT in greater detail.
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PMID:Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines. 1261 42

Kahalalide F (KF) is a novel antitumor drug of marine origin under clinical investigation. KF showed a potent cytotoxic activity against a panel of human prostate and breast cancer cell lines, with IC(50) ranging from 0.07 micro M (PC3) to 0.28 micro M (DU145, LNCaP, SKBR-3, BT474, MCF7). Importantly, nontumor human cells (MCF10A, HUVEC, HMEC-1, IMR90) were 5-40 times less sensitive to the drug (IC(50) = 1.6-3.1 micro M). KF cytotoxicity did not correlate with the expression level of the multidrug resistance MDR1 and of the tyrosine kinase HER2/NEU, and only slightly by the anti-apoptotic BCL-2 protein. KF action was triggered rapidly by short pulse treatments (15 min caused 50% maximum cytotoxicity). Neither a general caspase inhibitor (Z-VAD-fmk) nor transcription or translation inhibitors (actinomycin D, cycloheximide) blocked KF action. Flow cytometry analysis revealed that KF induced neither cell-cycle arrest nor apoptotic hypodiploid peak. Using mitochondrial (JC-1)- and lysosomal (LysoTracker Green, Acridine Orange)-specific fluorophores, we detected loss of mitochondrial membrane potential and of lysosomal integrity following KF treatment. Confocal laser and electron microscopy revealed that KF-treated cells underwent a series of profound alterations including severe cytoplasmic swelling and vacuolization, dilation and vesiculation of the endoplasmic reticulum, mitochondrial damage, and plasma membrane rupture. In contrast, the cell nucleus showed irregular clumping of chromatin into small, condensed masses, while chromatin disappeared from other nuclear domains, but the nuclear envelope was preserved and no DNA degradation was detected. Together, these data indicate that KF induces cell death via oncosis preferentially in tumor cells.
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PMID:Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. 1455 5

Multi drug resistance (MDR) is a major obstacle for cancer therapy. The three major candidates accounting for the development of MDR in acute myeloid leukaemia (AML) are multi drug resistance gene (MDR1), multi drug resistance-related protein gene (MRP1) and lung resistance protein gene (LRP). So far, the differential impact of resistance gene expression on treatment outcome in AML is not clear. Therefore, we examined MDR1, MRP1 and LRP gene expression at diagnosis in 331 adult AML patients in the context of other known prognostic factors, such as age, disease status, cytogenetics and FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication mutational status. Median observation time was longer than 5 years [64.1 months (40.0-87.6)]. MDR1 expression proved to be an independent prognostic factor for outcome of induction therapy (P <0.001) and overall survival (P=0.02), whereas MRP1 expression was an independent predictor for disease-free survival (P=0.01) in the multivariate analysis. This prognostic impact of both resistance genes was also found in patients with intermediate risk cytogenetics. LRP expression, however, had no impact on treatment outcome in AML. Our study shows that resistance gene expression should be considered together with age, cytogenetics and FLT3 mutational status for risk-adapted treatment strategies in AML in the future.
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PMID:MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. 1566 34

Genomic microarray systems can simultaneously provide substantial genetic and chromosomal information in a relatively short time. We have analyzed genomic DNA from frozen sections of 30 cases of primary glioblastomas by GenoSensor Array 300 in order to characterize gene amplifications, gene deletions, and chromosomal information in the whole genome. Genes that were frequently amplified included RFC2/CYLN2 (63.3%), EGFR (53.3%), IL6 (53.3%), ABCB1 (MDR1) (36.7%), and PDGFRA (26.7%). Genes that were frequently deleted included (56.7%), FGFR2 (66.7%), MTAP (60.0%), DMBT1 CDKN2A (p16)/MTAP (50.0%), PIK3CA (43.3%), and EGR2 (43.3%), but deletion of RB1 or TP53 was rarely detected. Chromosomal gains were observed frequently for 7q (33.3%), 7p (20.0%), and 17q (13.3%). Loss of the 10q was frequently detected in 13 of 30 cases (46.7%). Loss of the entire chromosome 10 was seen in 9 of 30 cases (30.0%), and was often accompanied by EGFR amplification (7 cases, 77.8%). The GenoSensor Array 300 proved to be useful for identification of genome-wide molecular changes in glioblastomas. The obtained microarray profile can also yield valuable insight into the molecular events underlying carcinogenesis of brain tumors and may provide clues about clinical correlations, including response to treatment.
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PMID:Genetic analysis of human glioblastomas using a genomic microarray system. 1569 66

Progress in the treatment of colon cancer depends on the development of target-based molecules built on an improved understanding of the molecular biology of the disease. Defining end points for chemotherapy resistance is needed as drug resistance develops quickly and patients demonstrate variation in response to chemotherapy. Many techniques that measure a marker's preponderance have been developed including biochemical, immunohistochemical, genomics, proteomics or a combination thereof. However, standardization of these techniques that measure either genes or their protein products is urgently needed. This article reviews several markers (TS,TP, DPD, FT, EGFR, VEGF, CD44v6, TRAIL, microsatellite instability, allelic deletions, oncogenes and suppressor genes [c-myc, Ki-Ras, p53, p21, Topo I, Topo IIalpha, Fos, hMLH1, Bcl-2/Bax and MDR1], MDR-related proteins [Pgp, MRP and LRP], genomic polymorphisms [XPD, ERCC1, GSTP1 and TS 3 -UTR] and COX-;2) that influence DNA metabolism, DNA damage, programmed cell death, the immune or vascular system, or lead to mutations. When combined together and tested by newly developed genomic and proteomic approaches, many of these markers provide a more sensitive indicative predictor of response than when evaluated separately or by older biochemical, immunohistologic or morphologic methods. A global approach involving the simultaneous testing of several predictive multimarkers will provide critical information for improving chemotherapy to alleviate suffering from this disease.
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PMID:Molecular markers that predict response to colon cancer therapy. 1593 13


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