Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Forty-seven ovarian cancer cases in which 20 were previously treated with cisplatin (cisPt) based chemotherapy, were checked for in vitro chemosensitivity using MTT assay. The drugs included in the study were cisPt, adriamycin (ADR), epirubicin (EPR) and etoposide (ETO). The logarithemic concentrations (0.1, 1.0, 10.0 and 100.0 micrograms/ml) of these drugs were used in the MTT assay. The IC50 values for these drugs in the above tumor samples were calculated. The effect of pretreatment with cisPt based chemotherapy on the emergence of drug resistance, expression of p53 protein (detected using immunohistochemical method by employing monoclonal antibody to p53) and intracellular glutathione (GSH) levels was also studied. Our results demonstrated the superiority of EPR in terms of its efficacy as compared to the other drugs used in the study. EPR was effective in both, previously cisPt-exposed and cisPt-unexposed ovarian cancer cases indicating its importance as a second line chemotherapy in the refractory ovarian carcinoma cases. Pre-exposure to cisPt based chemotherapy appears to result in the emergence of cisPt resistance, elevated intracellular GSH levels as well as p53 positivity. A statistically significant correlation was also observed between ADR and EPR resistance and p53 positivity (P < 0.01 and 0.05 respectively).
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PMID:Effect of cisplatin-based chemotherapy on emergence of cisplatin resistance, and its correlation with intracellular glutathione levels and accumulation of p53 protein in human ovarian cancer. 1094 37

We examined p53 protein stability and DNA damage-induced p53-dependent responses in a human leukemic CEM cell line and two teniposide-resistant sublines, CEM/VM-1 and CEM/VM-1-5 ( approximately 40 and 400-fold resistant to teniposide, respectively). Although all cell lines contain the same p53 mutations at codons 175 (Arg-->His) and 248 (Arg-->Gln), the constitutive levels of p53 were progressively increased with the resistance of the cells to teniposide. By pulse-chase experiments, we found that the half-lives of mutant p53 protein were approximately 12, 17, and >30 h in CEM, CEM/VM-1, and CEM/VM-1-5 cells, respectively. The prolonged half-lives of p53 in these cells is consistent with the fact that the protein harbors the indicated mutations. Of note, however, is the fact that the increased p53 protein half-lives in the two drug-resistant cell lines corresponds to a proportional decrease in MDM2 protein levels but an increase in p53-MDM2 binding interactions. This suggests that MDM2-mediated p53 degradation may be altered in our leukemic cell lines. The DNA damage-induced p53 response is fully functional in the drug-sensitive CEM cells containing a mutant p53, but this pathway is attenuated in the drug-resistant cells. Specifically, while the mutant p53 was phosphorylated at serine-15 in response to ionizing radiation in all these cell lines, mutant p53 induction in response to teniposide or ionizing radiation and induction of the p53-target genes, p21 and GADD45 only occurred in the drug-sensitive CEM cells. As assessed by MTT cytotoxicity assay, CEM cells were also significantly more sensitive to ionizing radiation, compared to the drug-resistant cell lines, and this correlated with p53 induction. Collectively, these results suggest that changes in constitutive mutant p53 protein levels, p53-MDM2 binding interactions, and altered regulation of the DNA damage-inducible p53-dependent pathway may play a role in drug- and radiation-responsiveness in these cells.
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PMID:Differences in mutant p53 protein stability and functional activity in teniposide-sensitive and -resistant human leukemic CEM cells. 1104 88

Allyl sulfur compounds play a major role in the chemoprevention against carcinogenesis. The present study compared the antiproliferative effects of diallyl sulfide (DAS), diallyl disulfide (DADS) and garlic extract on p53-wild type H460 and p53-null type H1299 non small cell lung cancer cells (NSCLC). The DAS and DADS treatment of both H460 and H1299 cells resulted in the highest numbers of cells in apoptotic state as measured by acridine orange staining, however, garlic extract treatment did not induce any significant apoptotic cells by MTT assay. DADS was found to be more effective in inducing apoptosis on NSCLC. The level of p53 protein in H460 cell was increased following DADS treatment. DAS and garlic extract treatment of H460 cells induced a rise in the level of Bax and a fall of Bcl-2 level. These results demonstrate that DAS, DADS and garlic extract are effective in reduction of anti-proliferative gene in NSCLC and suggest that modulation of apoptosis-associated cellular proteins by DAS, DADS and garlic extract may be the mechanism for apoptosis which merit further investigation as potential chemoprevention agents.
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PMID:Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines. 1104 43

Adenophora triphylla (AT), an oriental medicinal plant, was extracted using water and several organic solvents and each fraction was assayed for its tumoricidal effects on human Jurkat T cells with 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT). The influence on induction of apoptosis and G1 arrest was also examined. The ethyl acetate fraction showed the most pronounced inhibitory effects on proliferation of Jurkat T cells. Apoptosis was induced in line with up-regulation of FasL, tyrosine phosphorylation and c-fos mRNA levels. Arrest in G1 of the cell cycle was observed in A2780 cells with a wild type p53 gene but not HT-29 cells with a mutant p53 gene. Modifying effects of AT on cell turnover and glutathione(GSH) levels in vivo were also investigated in the stomach of rats given 150 mg/kg of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by gavage and then fed a diet supplemented with 5% or 1% pulverized AT and 0.5% or 0.2% ethylacetate-extracted AT for 42 hours. The 5% AT and both of the ethylacetate fractions caused significant reduction in proliferating cell nuclear antigen (PCNA)-labeling in the glandular stomach epithelium as compared with the value for the MNNG alone group. In addition, the treatments significantly increased the gastric GSH levels. These results suggest that AT could be a chemopreventive agent against gastric cancer.
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PMID:Suppressive effects of Adenophora triphylla extracts on in vitro tumor cell growth and in vivo gastric epithelial proliferation. 1106 47

In an attempt to ameliorate the chemotherapy associated normal cell toxicity, in this study a known antioxidant, grape seed proanthocyanidin extract (GSPE) using Chang liver cells has been used. Chang liver cells were treated in vitro with idarubicin (Ida) (30 nM) and 4-hydroxyperoxycyclophosphamide (4-HC) (1 microg/ml) with or without proanthocyanidin (25 microg/ml). The cells were grown in vitro and the growth rate of the cells were determined using MTT assay. The results showed that the GSPE decreased growth inhibitory effects of Ida and 4-HC on Chang liver cells in vitro. Since these chemotherapeutic agents are known to induce apoptosis in the target cells, these cells were also analyzed for presence of apoptotic cells using flow cytometry. The GSPE decreased the number of apoptotic cell population induced by either chemotherapy. In an attempt to determine the mechanisms of ameliorating effects of proanthocyanidin, the expression of apoptosis/cell cycle/growth related genes, Bcl-2, p53 and c-myc was determined in the treated and control cells using Western blotting or reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. There was an increased expression of Bcl-2 in the cells treated with GSPE. However, there was a significant decrease in the expression of other cell cycle related genes such as p53 and c-myc in these cells following treatment with GSPE. Thus, these results indicate that proanthocyanidin can be a potential candidate to ameliorate the toxic effects associated with chemotherapeutic agents used in treatment of cancer.
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PMID:Chemopreventive effects of grape seed proanthocyanidin extract on Chang liver cells. 1115

A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)-fluorouracil (FU)-folinic acid (FA) combination and by CPT11-FU-FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU-FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC(50)) of the double association without that drug divided by the IC(50)of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU-FA.
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PMID:Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines. 1120 57

Organotin compounds, particularly tri-organotin, have demonstrated cytotoxic properties against a number of tumor cell lines. On this basis, triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), a quinolizidine derivative, was synthesized and developed as a potential antitumor agent. This tin-derived compound exhibited potent antiproliferative effects on three different human cancer cell lines: teratocarcinoma of the ovary (PA-1), colon carcinoma (HCT-8) and glioblastoma (A-172). Cytotoxic activity was assessed by MTT and cell count assays during time course experiments with cell recovery after compound withdrawal. Significant cell growth inhibition (up to 95% in HCT-8 after 72 h of exposure), which also persisted after drug-free medium change, was reported in all the cell lines by both assays. In addition, the cytocidal effects exerted by IST-FS 29 appeared more consistent with necrosis or delayed cell death, rather than apoptosis, as shown by morphologic observations under light microscope, DNA fragmentation analysis and flow cytometry. In the attempt to elucidate whether this compound might affect genes playing a role in G1/S phase transition, the expressions of p53, p21(WAF1), cyclin D1 and Rb, mainly involved in response to DNA-damaging stress, were analyzed by Western blot. Heterogeneous patterns of expression during exposure to IST-FS 29 were evidenced in the different cell lines suggesting that these cell-cycle-related genes are not likely the primary targets of this compound. Thus, the present data seem more indicative of a direct effect of IST-FS-29 on macromolecular synthesis and cellular homeostasis, as previously hypothesized for other organotin complexes.
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PMID:Antiproliferative activity and interactions with cell-cycle related proteins of the organotin compound triethyltin(IV)lupinylsulfide hydrochloride. 1124 20

We have developed an in vitro model of 38 T-lymphoblastic leukemia lines resistant to cytosine arabinoside (ara-C) and L-asparaginase (ASNase). Of these, 26 cell lines resistant to both drugs, 6 resistant to ara-C, and 6 resistant to ASNase were isolated. In 18 of these cell lines, all randomly selected, resistance to ara-C, ASNase and gamma radiation was documented by the MTT and trypan blue assays, as well as flow cytometry with Annexin V and propidium iodide (PI) staining. In these lines, p53, p21WAF1, and bcl-2 levels were measured by ELISA. Results show that P21WAF1 upregulation following p53 induction did not occur, suggesting that p53 function may be lost. Moreover, the data imply that upregulation of bcl-2 is critical in the development of resistance to ara-C and ASNase in these leukemic lines. In the CEM/0 parent line, p53 maintained its ability to interact with its DNA binding site as documented by the electrophoretic mobility shift assay (EMSA). But in one single- and one double-resistant leukemic cell line examined, p53 was not shown to maintain this ability. We conclude that double-resistant clones to ara-C and ASNase are refractory to both drugs, providing an excellent leukemic model to investigate the multiple-drug resistance.
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PMID:Development of a double-drug-resistant human leukemia model to cytosine arabinoside and L-asparaginase: evaluation of cross-resistance to other treatment modalities. 1129 23

To determine whether the expression of p53, p21, bcl-2 or Ki-67 in cancer cells is predictive of chemosensitivity, immunohistochemical examination of these factors and chemosensitivity assays were performed on colon and gastric cancer specimens. Chemosensitivity tests were performed using CDDP, 5-FU, MMC, or ADR and inhibition rate (IR) was calculated by MTT assay. Before exposure to anticancer drugs, the samples were investigated immunohistochemically for expression of the above factors and after anticancer drug exposure by TUNNEL staining, for the presence of apoptotic cells. With 5-FU and MMC, the apoptotic index was well correlated with IR, so their effects were related to apoptosis. Moreover, with these two agents, the p53 labeling index (LI) was inversely correlated with IR and p21-LI showed a good correlation with IR. We therefore concluded that immunohistochemical studies for p53 and p21 were useful for predicting the chemosensitivities of colon and gastric cancer to MMC and 5-FU.
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PMID:Correlation of immunohistochemical p53 labeling index with inhibition rate in chemosensitivity test in gastric and colon cancer. 1129 39

B-cell chronic lymphocytic leukemia (CLL) is the most common type of leukemia diagnosed in the Western Hemisphere and remains incurable with currently available therapy. In an attempt to identify new potential therapy for CLL, we explored the pre-clinical activity of gemcitabine in human B-CLL cells (n =11). Mononuclear cell isolates were exposed to varying concentrations of gemcitabine (0.01-100 microM) for 4, 24, and 96 h. Viability, as determined by the tetrazolium salt (MTT) assay, after a 4 h incubation with gemcitabine declined in 6 of 8 (75%) evaluable patients at a concentration < 30 microM (a physiologically attainable level), and 3 of 8 of the B-CLL cells had an LC50 (concentration where 50% loss of viability is observed) < 30 microM. At 4 days of drug exposure, 82% (9/11) of patients had an LC50 < 30 microM. Annexin-V/propidium iodine staining demonstrated apoptosis in CLL cells exposed to 30 microM of gemcitabine. Examination of changes in apoptosis related proteins demonstrated no significant change in bcl-2, bax or p53 protein expression with gemcitabine (23 microM) at 4, 24, or 48 h. These data demonstrate that gemcitabine has pre-clinical activity in B-CLL and supports its exploration as a single agent and in combination with other active agents in this disease.
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PMID:Gemcitabine demonstrates in vitro activity against human B-cell chronic lymphocytic leukemia. 1133 14


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