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)

Multiple drug resistance occurs when cells fail to respond to chemotherapy. Although it has been established that the drug efflux protein P-glycoprotein protects the brain from xenobiotics, the mechanisms involved in the regulation of expression of multiple drug resistance genes and proteins are not fully understood. Re-entry into the cell cycle and integrity of the p53 signaling pathway have been proposed as triggers of multiple drug resistance expression in tumor cells. Whether this regulation occurs in non-tumor CNS tissue is not known. Since multiple drug resistance overexpression has been reported in glia and blood vessels from epileptic brain, we investigated the level of expression of multidrug resistance protein, multidrug resistance-associated proteins and lung resistance protein in endothelial cells and astrocytes isolated from epileptic patients or studied in situ in surgical tissue samples by double label immunocytochemistry. Reverse transcriptase-polymerase chain reaction and Western blot analyses revealed that multiple drug resistance, multidrug resistance protein, and lung resistance protein are expressed in these cells. Given that lung resistance proteins have been reported to be preferentially expressed by tumors, we investigated expression of tumor suppressor genes in epileptic cortices. The pro-apoptotic proteins p53 and p21 could not be detected in "epileptic" astrocytes, while endothelial cells from the same samples readily expressed these proteins, as did normal brain astroglia and normal endothelial cells. Other apoptotic markers were also absent in epileptic glia. Our results suggest a possible link between loss of p53 function and expression of multiple drug resistance in non-tumor CNS cells.
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PMID:Relationship between expression of multiple drug resistance proteins and p53 tumor suppressor gene proteins in human brain astrocytes. 1456 21

Drug resistance, intrinsic or acquired, is a problem for all chemotherapeutic agents. In this review, we examine numerous strategies that have been tested or proposed to reverse drug resistance. Included among these strategies are approaches targeting the apoptosis pathway. Although the process of apoptosis is complex, it provides several potential sites for therapeutic intervention. A variety of targets and approaches are being pursued, including the suppression of proteins inhibiting apoptosis using antisense oligonucleotides (ASOs), and small molecules targeted at proteins that modulate apoptosis. An alternate strategy is based on numerous studies that have documented methylation of critical regions in the genome in human cancers. Consequently, efforts have been directed at re-expressing genes, including genes that affect drug sensitivity, using 5-azacytidine and 2'-deoxy-5-azacytidine (DAC, decitabine) as demethylating agents. While this strategy may be effective as a single modality, success will most likely be achieved if it is used to modulate gene expression in combination with other modalities such as chemotherapy. At a more basic level, attempts have been made to modulate glutathione (GSH) levels. Owing to its reactivity and high intracellular concentrations, GSH has been implicated in resistance to several chemotherapeutic agents. Several approaches designed to deplete intracellular GSH levels have been pursued including the use of buthionine-(S,R)-sulfoxime (BSO), a potent and specific inhibitor of gamma-glutamyl cysteine synthetase (gamma-GCS), the rate-limiting step in the synthesis of GSH, a hammerhead ribozyme against gamma-GCS mRNA to downregulate specifically its levels and targeting cJun expression to reduce GSH levels. Alternate strategies have targeted p53. The frequent occurrence of p53 mutations in human cancer has led to the development of numerous approaches to restore wild-type (wt) p53. The goals of these interventions are to either revert the malignant phenotype or enhance drug sensitivity. The approach most extensively investigated has utilized one of several viral vectors. An alternate approach, the use of small molecules to restore wt function to mutant p53, remains an option. Finally, the conceptually simplest mechanism of resistance is one that reduces intracellular drug accumulation. Such reduction can be effected by a variety of drug efflux pumps, of which the most widely studied is P-glycoprotein (Pgp). The first strategy utilized to inhibit Pgp function relied on the identification of non-chemotherapeutic agents as competitors. Other approaches have included the use of hammerhead ribozymes against the MDR-1 gene and MDR-1-targeted ASOs. Although modulation of drug resistance has not yet been proven to be an effective clinical tool, we have learned an enormous amount about drug resistance. Should we succeed, these pioneering basic and clinical studies will have paved the road for future developments.
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PMID:Strategies for reversing drug resistance. 1457 55

Chemoresistance is a major problem in the treatment of hepatocellular carcinoma. Certain p53 mutants may enhance drug resistance in cancer cells. To determine whether two frequently occurring p53 mutants, R248Q and R273C, would increase the drug resistance of liver cancer cells, stable cell lines expressing these specific p53 mutants were established by transfecting the p53-null Hep3B cells with mutant p53 expression vectors, and then treating them with the anticancer drugs doxorubicin and paclitaxel. The cells expressing the p53 mutant, R248Q, but not R273C, displayed cross-resistance to both drugs, in contrast to the control cells expressing the vector alone. Moreover, both the expression and the activity of the multiple drug resistance gene product, P-glycoprotein, were elevated in p53 mutant R248Q-expressing cells. Reduced uptake of doxorubicin was also observed in the R248Q-expressing cells. These results suggest that expression of the p53 mutant, R248Q, in liver cancer cells may enhance their drug resistance and that upregulation of P-glycoprotein activity may contribute to this protective effect.
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PMID:Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. 1500 24

The purpose of this study was to investigate the prognostic effects of four biological markers, BCL2, TP53, Ki-67, and P-glycoprotein, and their possible clinical relevance in addition to the international prognostic index (IPI) in diffuse large B-cell lymphoma (DLBCL). A total of 405 patients with aggressive lymphoma, stage II-IV, between 18 and 67 years, were randomized in a trial comparing CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). Of these, 267 cases were classified as DLBCL, with adequate paraffin blocks available in 207 cases, enabling immunohistochemical assessment of the expression of BCL2, TP53, P-glycoprotein, and Ki-67. In a multivariate analysis, stratified for IPI, high BCL2 expression (>10%) low (<60%) expression of Ki-67, and high TP53 protein expression (>75%) were shown to provide additional prognostic information with regard to overall or failure-free survival. We found no association between expression of P-glycoprotein and outcome. Assessment of BCL2 positivity might be introduced as part of the routine investigation in patients with DLBCL, but further studies are necessary to confirm the clinical relevance of Ki-67 and TP53 expression.
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PMID:Assessment of biological prognostic factors provides clinically relevant information in patients with diffuse large B-cell lymphoma--a Nordic Lymphoma Group study. 1508 85

Gallbladder cancer (GBC) is the most common biliary tract malignancy. There is a tremendous regional variability in its incidence. Risk factors include genetic susceptibility, gender, presence of gallstones, chronic biliary infections, diet and some anatomical anomalies. Several genetic abnormalities have been described which may be aetiologically important as well as carry prognostic significance. These include mutations in the proteins K-RAS and P53, and altered expression of P-glycoprotein, COX-2 and epidermal growth factor receptor. Most patients present at an advanced stage, overall prognosis is very poor. TNM stage and the extent of surgical resection are the most important prognostic factors. Surgery is the only curative therapy reserved for patients with early-stage disease. The role of adjuvant therapy is not fully defined. Patients with advanced disease are managed with systemic chemotherapy that is primarily palliative. Although 5-fluorouracil alone, or in combination, has been most commonly utilised, there is much greater enthusiasm for the combination of cisplatin and gemcitabine. The availability of better drugs and combinations may affect the use of chemotherapy in neoadjuvant and adjuvant settings. Novel targeted therapies require exploration alone or in combination with chemotherapy.
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PMID:Gallbladder cancer: current status. 1516 72

Cepharanthin (CEP) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. CEP is reported to inhibit drug resistance by inhibiting P-glycoprotein, a drug efflux pump, and recently to induce apoptosis. In the present study, we examined the effects of CEP as an inhibitor of adriamycin (ADR) resistance on ADR-induced apoptosis and necrosis. First, we established p53-deficient ADR-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. Resistant cells showed a higher level of intracellular glutathione peroxidase activity than parent cells. P-glycoprotein was overexpressed in resistant cells. The intracellular ADR level of resistant cells was lower than that of parent cells. One micro g/ml CEP eliminated the degradation of intracellular ADR of resistant cells; that is, to a level equivalent to that of the parent cells. CEP of 0.5 micro g/ml, which was not cytotoxic when used alone, significantly increased the ADR sensitivity of resistant cells, to a level similar to the parent cell level. Isosorbide 5-mononitrate, a potential nitric oxide-generation agent, combined with CEP further increased the ADR sensitivity of resistant cells, indicating a synergistic effect of CEP and isosorbide 5-mononitrate on ADR cytotoxicity. Time-lapse microscopic observation revealed that ADR dominantly induced apoptosis much more than necrosis for both parent and resistant cells, and that the use of 0.5 micro g/ml CEP with ADR synergistically accelerated apoptosis in resistant cells. Finally, we clarified the property by which CEP synergistically accelerates ADR-induced apoptosis. This property might be a new mechanism that explains how CEP overcomes ADR resistance.
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PMID:Cepharanthin enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. 1520 88

KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.
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PMID:Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A). 1533 56

During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT-70, isolated from the stem bark of Calophyllum brasiliense collected in Brazil, significantly inhibits the growth of leukemic cells. GUT-70, characterized as a tricyclic coumarin, 5-methoxy-2,2-dimethyl-6-(2-methyl-1-oxo-2-butenyl) -10-propyl-2H,8H-benzo[1,2-b;3,4-b']dipyran-8-one (C(23)H(26)O(5)), inhibited all 6 human leukemic cell lines evaluated, including the P-glycoprotein overexpressing cell line, in a concentration and time-dependent manner with IC(50) values from 2-5 microM. Furthermore, GUT-70 did not inhibit colony formation by normal hematopoietic progenitors up to 30 microM and also did not inhibit the proliferation of normal human hepatocytes up to 30 microM. GUT-70 activated the caspase 2, 3, 8 and 9, and induced the apoptosis in leukemic cells, which was inhibited by caspase inhibitors. GUT-70 induced anti-leukemic effects independent of the p53-p2l(WAFl/CIP1) pathway and increased the overall expression of p27(KIP1) and p57(KIP2), to stop the cell cycle at the G(1)/S transition. Thus, a novel anti-cancer drug, GUT-70 isolated from the stem bark of C. brasiliense induces caspase-mediated and p53-independent apoptosis to overcome multidrug resistance and may become a potent leukemia therapeutics.
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PMID:Inhibition of leukemic cell growth by a novel anti-cancer drug (GUT-70) from calophyllum brasiliense that acts by induction of apoptosis. 1538 57

The potential anti-tumour activity of non-steroidal anti-inflammatory drugs (NSAIDS) has been previously discussed. This study was undertaken to assess the possible anti-tumour activity of the cyclooxygenase-2 (COX-2) inhibitor; celecoxib in an animal model of mammary carcinoma; the solid Ehrlich carcinoma (SEC). The possibility that celecoxib may modulate the anti-tumour activity of doxorubicin on the SEC was also studied. Some of the possible mechanisms underlying such modulation were investigated. The anti-tumour activity of celecoxib (25 mg kg(-1)), diclofenac (12.5 mg kg(-1)) and doxorubicin (2 mg kg(-1)) either alone or in combination were investigated on SEC in vivo through the assessment of tumour growth delay (TGD) and tumour volume (TV), changes in tumour DNA content and nitric oxide (NO) levels, immunohistochemical staining of the tumour suppressor gene product; p53 histopathological examination and determination of apoptotic index of SEC. In addition, the influence of these drugs on the DNA fragmentation pattern of Ehrlich carcinoma cells (ECC) was studied. It was found that both celecoxib and diclofenac lack the anti-tumour activity on SEC. In addition there was a significant increase in doxorubicin anti-tumour activity when administered in combination with celecoxib. Moreover, it was found that both celecoxib and diclofenac have the potential to inhibit the function of P-glycoprotein (P-gp) in ECC using rhodamine uptake and efflux assays. Therefore, the current study suggested the chemosensitizing potential of celecoxib in the SEC animal model of mammary tumour, which could be explained in part on the basis of inhibition of P-gp function, with possible enhancement of doxorubicin anti-tumour activity.
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PMID:The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of doxorubicin? 1545 69

The protein kinase C (PKC) family consists of serine/threonine protein kinases that play important roles in signal transduction, cell proliferation, and tumor formation. Recent studies found that PKCs are commonly overexpressed in human tumors, including soft tissue sarcoma (STS). Overexpression of PKCs contributes to invasion and migration of tumor cells and induction of angiogenesis. PKC can also phosphorylate the multidrug resistance (MDR) gene-encoded P-glycoprotein and induce MDR phenotype. Our previous studies showed that mutation of p53 enhanced STS metastasis and mediated the MDR phenotype. Restoring wild type (WT) p53 in STS cells containing mutant p53 sensitized the cells to chemotherapy. In the present study, we found that PKCalpha protein expression is inhibited by WT p53 partly due to reduced PKCalpha mRNA expression in STS cells, but p53 does not affect PKCalpha mRNA stability. Deletion and mutation analysis of the PKCalpha promoter fused to the luciferase reporter gene identified a Sp1 binding site (-244/-234) in the PKCalpha promoter that is required for p53-mediated inhibition of PKCalpha promoter activity. More importantly, PKCalpha phosphorylates and activates MDR1 P-glycoprotein, whereas inhibition of PKCalpha by p53 leads to decreased MDR1 phosphorylation in STS cells, which sensitizes STS cells to chemotherapeutic agents. These data indicate that WT p53 may resensitize STS to chemotherapeutic agents by reducing MDR1 phosphorylation via transcriptional repression of PKCalpha expression. Thus, molecular-based therapies targeting mutant p53 and PKCalpha may be an effective new strategy to improve chemotherapeutic efficacy in STS.
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PMID:Transcriptional repression of protein kinase Calpha via Sp1 by wild type p53 is involved in inhibition of multidrug resistance 1 P-glycoprotein phosphorylation. 1556 62


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