Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A combination of 5-fluorouracil (5-FU) and cisplatin (cis-Diamminedichloroplatinum(II); CDDP) was administered to CDDP-sensitive (A2780) and -resistant (2780CP) human ovarian cancer cell lines in vitro in order to investigate the effects of 5-FU pretreatment on CDDP cytotoxicity, removal of DNA-bound platinum (Pt-DNA) and cellular glutathione (GSH) level. The cells were incubated with various doses of 5-FU for 24 hours, and then exposed to various doses of CDDP after a drug-free interval of 24 hours. Pretreatment with 5-FU (0.5 - 2.0 microg/ml) augmented the cytotoxicity of CDDP in 2780CP cells, but did not affect A2780 cells. 2780CP cells lost 23.0 to 41.9% of their total Pt-DNA determined by flameless atomic absorption spectrophotometry at 6 to 24 hours after exposure to 10.0 microg/ml CDDP alone; nevertheless, 1.0 microg/ml 5-FU pretreatment caused a significant delay in removal of Pt-DNA (3.8, 1.5 and 7.2% at 6, 12 and 24 hours after exposure to CDDP, respectively). At 24 hours after 15.0 microg/ml CDDP exposure, 2780CP cells pretreated with 5-FU lost only 15.7% of their total Pt-DNA, although the platinum removal rate with CDDP alone was 28.4%. The GSH levels in 2780CP cells were similar in the presence or absence of 5-FU pretreatment. These data indicated that 5-FU pretreatment enhances the cytotoxicity of CDDP and reverses CDDP resistance in 2780CP cells and that its mechanism is related to the inhibitory effect of 5-FU on DNA repair, and not to cellular GSH levels.
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PMID:Pretreatment with 5-fluorouracil enhances cytotoxicity and retention of DNA-bound platinum in a cisplatin resistant human ovarian cancer cell line. 1172 8

Human ovarian cancer cell lines derived from A2780 by stepwise exposure to increasing cisplatin concentrations show progressive resistance to cisplatin. Previous studies have shown increased cellular glutathione and elevated steady-state expression of gamma-glutamylcysteine synthetase (gamma-GCS) and of the transcription factor c-Jun, all in proportion to the level of resistance in the resistant cells. We hypothesized that c-Jun was an important locus of control of the detoxicating enzymes mediating resistance, and that resistance reversal would be achieved by specific inhibition of this mechanism. A2780 (sensitive) and C30 (resistant) cells were treated with a 20-mer c-jun phosphorothioate antisense oligodeoxynucleotide (ISIS 10582, 1 microM), and a decrease in steady-state c-jun mRNA was demonstrated in the resistant cells. The expression of gamma-GCS mRNA was down-regulated and the cellular level of glutathione was decreased in C30 cells. No change in gamma-GCS expression occurred in A2780 cells. Using the microtetrazolium (MTT) cytotoxicity assay, we determined that the c-jun antisense decreased the IC50 value for cisplatin in C30 cells from 18.2 to 3.7 microM, and had a substantially smaller effect in A2780 cells. To determine if c-jun overexpression alone could confer resistance to the sensitive cell line, we transiently transfected A2780 cells with a c-jun expression vector. The transfected cells exhibited a 10.7-fold elevation of glutathione (GSH) content, a 9.2-fold increase in c-Jun protein content, and a 2-fold increase in the IC50 for cisplatin. These data suggest that altered regulation of transcription factor expression contributes to the acquired resistance phenotype in these ovarian cancer cells, and provide a novel potential target for therapeutic intervention.
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PMID:Reversal of cisplatin resistance in human ovarian cancer cell lines by a c-jun antisense oligodeoxynucleotide (ISIS 10582): evidence for the role of transcription factor overexpression in determining resistant phenotype. 1200 73

The aim of this study is to establish anti-tumour potency of the new oral platinum drug JM216 and its metabolite JM118 in relation to the platinum (Pt)-DNA adduct formation, glutathione (GSH)-levels, and p53 status in human cancer cell lines with different sensitivities to cisplatin (CDDP). These parameters were studied in the CDDP sensitive human germ cell cancer cell line Tera and the small-cell lung cancer cell line GLC4 and their sublines with in vitro acquired CDDP resistance, Tera-CP and GLC4-CDDP, in a human ovarian cancer cell line transfected with mutant p53 (A2780/mt273) and with an empty vector as control (A2780/cmv), and in the intrinsic CDDP resistant human non-small-cell lung cancer cell line SW1573/S1 and colon carcinoma cell line Caco-2. Cytotoxicity was tested with the microculture tetrazolium (MTT)-assay. Pt-DNA adduct levels were assessed immunocytochemically. Quantitative analysis was performed by double fluorescence video microscopy. Results were correlated with GSH levels and p53 status of the cell lines. This study showed that both JM216 and JM118 can partially circumvent intrinsic and acquired resistance to CDDP. Drug-induced cytotoxicity only correlated negatively with GSH levels for JM216 and CDDP in the tested unselected cell lines. At equimolar basis, JM216 induced lower levels of Pt-DNA adducts in the various cell lines than JM118 and CDDP, whereas the JM118-induced amount and pattern of Pt-DNA adducts was comparable to CDDP. No difference in initial Pt-DNA adducts levels was observed between cell lines sensitive, acquired or intrinsic resistant to CDDP suggesting a Pt-resistance mechanism based on tolerance or increased repair, rather than decreased initial Pt-DNA adduct formation.
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PMID:JM216-, JM118-, and cisplatin-induced cytotoxicity in relation to platinum-DNA adduct formation, glutathione levels and p53 status in human tumour cell lines with different sensitivities to cisplatin. 1209 75

We have used structure-based design techniques to introduce the drug O(2)-[2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino) phenyl] 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), which is efficiently metabolized to potentially cytolytic nitric oxide by the pi isoform of glutathione S-transferase, an enzyme expressed at high levels in many tumors. We have used mouse embryo fibroblasts (MEFs) null for GSTpi (GSTpi(-/-)) to show that the absence of GSTpi results in a decreased sensitivity to PABA/NO. Cytotoxicity of PABA/NO was also examined in a mouse skin fibroblast (NIH3T3) cell line that was stably transfected with GSTpi and/or various combinations of gamma-glutamyl cysteine synthetase and the ATP-binding cassette transporter MRP1. Overexpression of MRP1 conferred the most significant degree of resistance, and in vitro transport studies confirmed that a GSTpi-activated metabolite of PABA/NO was effluxed by MRP1 in a GSH-dependent manner. Additional studies showed that in the absence of MRP1, PABA/NO activated the extracellular-regulated and stress-activated protein kinases ERK, c-Jun NH(2)-terminal kinase (JNK), and p38. Selective inhibition studies showed that the activation of JNK and p38 were critical to the cytotoxic effects of PABA/NO. Finally, PABA/NO produced antitumor effects in a human ovarian cancer model grown in SCID mice.
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PMID:Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. 1510 35

Three isomeric complexes, trans-[PtCl2(NH3)(2-methylpiperidine)], trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)], were prepared and their cytotoxicities against six ovarian cancer cell lines, three sensitive and three resistant to cisplatin, were measured. There were no significant differences in the cytotoxicities of the three isomers against these cell lines. The interactions of the three complexes with reduced glutathione (GSH) and with ubiquitin (Ub), as a model protein, were studied. The trans-[PtCl2(NH3)(2-methylpiperidine)] reacted approximately twice as slowly with GSH as did the other two isomers. In the 1:1 interactions of the three complexes with ubiquitin (Mr = 8565 amu), trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)] attained 100% modification while trans-[PtCl2(NH3)(2-methylpiperidine)] reached only less than 50% modification. Trans-[PtCl2(NH3)(2-methylpiperidine)] reacts significantly less efficiently with GSH and proteins than the other two isomers yet this is not reflected in the cytotoxicity values. These results indicate that for these complexes, in these cell lines, cytosolic detoxification probably does not play a dominant role in determining the cytotoxicity of the complexes.
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PMID:Preparation, cytotoxicity and interactions with nucleophiles of three isomeric transplatinum complexes containing methylpiperidine ligands. 1605 19

PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in water. Here we report structure-based optimization efforts resulting in three analogues with improved solubility and stability in aqueous solution. We sought to explain PABA/NO's physicochemical uniqueness among these four compounds, whose aminobenzoic acid precursors differ structurally only in the presence or absence of the N-methyl group and/or the position of the carboxyl moiety (meta or para). Studies revealed that PABA/NO's N-methyl-p-aminobenzoic acid substituent is bound to the dinitrobenzene ring via its carboxyl oxygen while the other three are linked through the aniline nitrogen. This constitutes a revision of the previously published PABA/NO structure. All four analogues reacted with GSH to produce bioactive nitric oxide (NO), but PABA/NO was the most reactive. Consistent with PABA/NO's potent suppression of A2780 human ovarian cancer xenograft growth in mice, it was the most potent of the four in the OVCAR-3 cell line.
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PMID:PABA/NO as an anticancer lead: analogue synthesis, structure revision, solution chemistry, reactivity toward glutathione, and in vitro activity. 1645 Oct 80

Recent studies have addressed the possibility of an association between polycystic ovaries and ovarian cancer. DNA damage is the first step of the carcinogenesis, and susceptibility to cancer, in general, is characterized by high DNA damage. Free radical-mediated DNA damage and impaired antioxidant defence have been implicated as contributory factors for the development of cancer. This study evaluates DNA damage (strand breakage, base oxidation, formamidopyrimidine DNA glycosylase (Fpg) sensitive sites), H2O2-induced DNA damage, a marker of DNA susceptibility to oxidation and glutathione (GSH) level, a powerful antioxidant, in women with polycystic ovary syndrome (PCOS). Women with PCOS showed a significant decrease in GSH level, a significant increase in DNA strand breakage and H2O2-induced DNA damage. Although Fpg-sensitive sites were higher in the PCOS group compared to the control group, the difference did not reach a statistically significant level. Significant correlations were found between free testosterone and DNA strand breakage (r = 0.46, p<0.01) and free testosterone and H2O2-induced DNA damage (r = 0.41, p<0.05). The data indicate that DNA damage and susceptibility of DNA to oxidative stress are increased in women with PCOS and may explain the association between PCOS and ovarian cancer.
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PMID:DNA damage, DNA susceptibility to oxidation and glutathione level in women with polycystic ovary syndrome. 1650 54

The treatment of alkylating cytotoxic drug cisplatin is often limited by high incidence rate of resistance. In the present study, the potential involvement of the transcription factor Nrf2 in determination of cisplatin cytotoxicity has been investigated. Nrf2-deficient murine embryonic fibroblasts showed increased cell death, cytotoxicity, and apoptosis in response to cisplatin treatment compared to wild-type cells. Cisplatin-resistant human ovarian cancer SK-OV cells, which are retaining 25-fold higher levels of GSH than murine fibroblasts, could be sensitized by inhibition of Nrf2. Transfection with Nrf2 siRNA into SK-OV cells resulted in severe degree of GSH depletion and exacerbated cytotoxicity following cisplatin treatment compared to scrambled RNA control. In conclusion, we propose that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to oxidants, cytotoxic chemicals, and radiation.
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PMID:Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. 1803 33

Pharmacological depletion of L-gamma-glutamyl-L-cysteinyl-glycine (GSH) has been implicated in the sensitization of cancer cells to alkylating agents and apoptosis. However, some types of cells do not induce apoptotic response following chemical depletion of GSH. In the present study, we report that murine embryonic fibroblasts (MEFs) can survive in the presence of GSH inhibitor L-buthionine-(S,R)-sulfoximine (BSO), even though most intracellular GSH was depleted. As a cellular adaptive mechanism, BSO treatment effectively activated the NF-E2-related factor 2 (Nrf2) pathway, which led to up-regulation of antioxidant enzymes in these cells through the extracellular signal-regulated kinase cascade. While nrf2-deficient MEFs lost the inducibility of antioxidant genes, which resulted in higher levels of reactive oxygen species accumulation, caspase-3 activation, and cell death than wild-type cells. Finally, nrf2-deficient cells can be more sensitized to doxorubicin-induced cell death by BSO pre-incubation, while wild-type cells were not. In addition, BSO-mediated cell death was facilitated by administering Nrf2 siRNA to chemoresistant human ovarian cancer cells. These results indicate that Nrf2 is the primary factor inducing the cell survival system under GSH depletion and that the effect of BSO as a chemosensitizer might be enhanced by inhibition of Nrf2.
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PMID:Adaptive response to GSH depletion and resistance to L-buthionine-(S,R)-sulfoximine: involvement of Nrf2 activation. 1858 29

The cytotoxic activity of bleomycin (BLM) was evaluated in cisplatin (CDDP)-sensitive (A2780) and -resistant (2780CP) human ovarian cancer cells, and the mechanism of increased antitumor activity of BLM in the 2780CP cells was investigated. Compared with the A2780 cells, the 2780CP cells exhibited a 4.5-fold increase in resistance to CDDP, but were 4.0-fold more sensitive to BLM. The cellular glutathione (GSH) levels in the 2780CP cells were significantly higher than those in the A2780 cells, however, GSH depletion in the 2780CP cells below the levels in the A2780 cells by using buthionine-[S,R]-sulfoximine (BSO) did not affect the sensitivity to BLM. BLM decreased 5-bromo-2'-deoxyuridine (BrdU) incorporation after 24-h exposure by 27.5%-90% compared to that of the untreated control at BLM doses of 25-500 ng/ml in the 2780CP cells, but only by 1.5% -45.8% in the A2780 cells. Furthermore, in the 2780CP cells, the percentage of S-phase cells markedly decreased, with an increase in G2/M-phase cells as determined by flow cytometry after exposure to BLM. The enhanced cytotoxity of BLM in CDDP-resistant 2780CP cells could be attributed to BLM-induced G2/M accumulation and significantly inhibited DNA synthesis, not to increased cellular GSH levels.
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PMID:Increased glutathione level is not involved in enhanced bleomycin sensitivity in cisplatin-resistant 2780CP cells. 1903 92


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