Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An in vitro model that might be relevant to cancer cell chemoresistance in vivo was generated by exposing the human lung carcinoma clonal cell line DLKP-SQ to 10 sequential pulses of pharmacologically attainable doses of doxorubicin. The resistant variant, DLKP-SQ/10p, was found to be cross-resistant to doxorubicin (10x), vincristine (43x), etoposide (3x), sodium arsenate (3x), paclitaxel (38x) [which could imply overexpression of P-glycoprotein (P-gp) and possibly increased multidrug resistance-associated protein activity] and 5-fluorouracil (4x), but slightly sensitized to carboplatin. Analysis of mRNA levels in the resistant variant revealed overexpression of mdr1 mRNA without significant alteration in mrp, Topo. IIalpha, GSTpi, dhfr or thymidylate synthase mRNA levels. Overexpression of the anti-apoptotic bcl-xL transcript and the pro-apoptotic bax mRNA was also detected but no alterations in bcl-2 or bag-1 mRNA levels were observed. Resistance to a P-gp-associated drug, doxorubicin, could be reversed with P-gp circumventing agents such as cyclosporin A and verapamil, but these substances had no effect on resistance to 5-fluorouracil. Overexpression of the pro-apoptotic bcl-xS gene in the DLKP-SQ/10p line partially reversed resistance not only to P-gp-associated drugs but also to 5-fluorouracil, indicating that the ratio of bcl family members may be important in determining sensitivity to chemotherapeutic drug-induced apoptosis.
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PMID:Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA. 1039 54

With the growing understanding of cytostatic drug-induced programmed cell death new drug-resistance mechanisms based on the altered ability of cells to die by apoptosis have been defined. At first, the sensitive and P-glycoprotein (P-gp)-related resistant cell lines were tested to induce apoptosis by a non-P-gp transported drug, such as cytosine arabinoside (ara-C). It was demonstrated that ara-C induces apoptosis in sensitive as well as in P-gp-related resistant cell lines, as expected. Furthermore, the role of bcl-2 and bcl-xL apoptosis inhibitors as well as bax expression (apoptosis inducer) in human sensitive leukemic cell lines (CCRF-CEM and HL-60) as compared to their resistant variants such as CCRF-CEM/ACT400, CCRF-CEM/VCR1000, HL-60/IDA40, HL-60/DNR250 was evaluated. In addition to the P-gp-related resistance, a possible multidrug resistance-associated protein (MRP) and the lung resistance protein (LRP)-related resistance were assessed by flow cytometry using the monoclonal antibodies 4E3.16, MRPr1 and LRP56. Furthermore, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test. Bcl-2 and bax were analyzed by both flow cytometry and ECL Western blot, bcl-xL by ECL-Western blot alone. Comparison of the two sensitive cell lines demonstrated different bcl-2, bax and bcl-xL patterns. The common characteristic was the increased expression of one of the apoptosis inhibitor proteins, such as bcl-2 or bcl-xL. The sensitive CCRF-CEM showed a high bax level, where a decrease of about 75% in resistant variants was measured. Compared to their sensitive counterpart HL-60, a low bax expression was analyzed, which increased in the resistant variant. The common characteristic of all resistant cell lines was the decreased expression of bax compared to bcl-2 or bcl-xL. In the P-gp-related resistant HL-60/DNR250 only an increase in bcl-xL was seen, whereas in the LRP-expressing as well as P-gp and MRP negative resistant HL-60/IDA40 both apoptotic inhibitor proteins bcl-2 and bcL-xL showed maximum increase, compared to the other resistant cell lines. The P-gp-related resistant cell lines CCRF-CEM/ACT400 and CCRF-CEM/VCR1000 also showed an increased expression of both bcl-2 and bcl-xL. Summarizing these results, it was shown that the examined sensitive human leukemic cell lines and their resistant variants demonstrated a different pattern of markers for preventing and promoting apoptosis. An association between P-gp and possible LRP-expressing leukemic cells as well as apoptosis-preventing markers (bcl-2, bcl-xL) seems to exist. The clinical relevance of the coexpression of various resistance mechanisms remains to be confirmed in large leukemia patient groups.
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PMID:Bcl-2, bax and bcl-xL expression in human sensitive and resistant leukemia cell lines. 1055 64

The effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-Adriamycin-OV-TLl6 antibody conjugate [P(GFLG)-ADR-Ab] on OVCAR-3 human ovarian carcinoma cells was studied. A nontargeted HPMA copolymer-ADR conjugate (P(GFLG)-ADR) and free ADR were the controls. The IC(50) doses were 0.65, 3.0, and 65 microM for free ADR, targeted P(GFLG)-ADR-Ab conjugate, and nontargeted P(GFLG)-ADR conjugate, respectively. These differences reflect the different mechanisms of cell entry of the compounds evaluated. Free ADR and HPMA copolymer-ADR conjugates had different impacts on the expression of MDR1, MRP, c-fos, c-jun, and bcl-2 genes which encode the P-glycoprotein (MDR1) and the multidrug resistance-associated protein (MRP) efflux pumps, and play an important role in cell death signaling pathways (c-fos, c-jun, and bcl-2). Whereas high doses of free ADR induced MDR1 gene expression, HPMA copolymer-bound ADR appeared to be without effect. On the contrary, expression of the MRP gene was not influenced by free ADR, whereas HPMA copolymer-ADR conjugates seemed to suppress the gene expression in a concentration-dependent manner. There were differences in the expression of c-fos, c-jun, and bcl-2 genes after the incubation of OVCAR-3 cells with free and HPMA copolymer-bound ADR indicating differences in activation of cell death signaling pathways.
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PMID:HPMA copolymer-anticancer drug-OV-TL16 antibody conjugates. 3. The effect of free and polymer-bound adriamycin on the expression of some genes in the OVCAR-3 human ovarian carcinoma cell line. 1061 22

To compare the clinical relevance of drug resistance factors in de novo acute myeloid leukemia (AML), we determined their relationship to both response to induction chemotherapy and survival of the patients in univariate as well as multivariate analyses. The drug resistance factors immunocytochemically studied in 111 patients at the time of diagnosis included the lung resistance protein (LRP), P-glycoprotein (P-gp), multidrug resistance protein (MRP1) and bcl-2. In the univariate analyses, age (P = 0.005), karyotype (P = 0.03), LRP (P = 0.003), P-gp (P = 0.02) and bcl-2 (P = 0.03) predicted for response to induction chemotherapy, whereas MRP1 had no predictive value. Age (P = 0.05), karyotype (P = 0.05) and LRP (P = 0.03) retained their predictive value in the multivariate logistic regression analyses. With regard to overall survival, age (P = 0. 008), karyotype (P = 0.006), LRP (P = 0.001) and P-gp (P = 0.01) were of prognostic value in the univariate Cox regression analyses but only age (P = 0.01), karyotype (P = 0.02) and LRP (P = 0.01) retained their prognostic significance in the multivariate analyses. A risk score based on the number of independent prognostic factors allowed division of patients into four groups with different outcome. In these groups, the complete remission rates were 93%, 75%, 47% and 33%, respectively, and median overall survival was 2.4, 1.2, 0.6 and 0.2 years, respectively. Thus, several drug resistance factors did predict outcome in the univariate analyses but LRP was the only drug resistance factor with independent predictive and prognostic significance. The proposed risk score might be useful for risk-adapted treatment in the future. Leukemia (2000) 14, 68-76.
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PMID:Drug resistance factors in acute myeloid leukemia: a comparative analysis. 1063 79

Cutaneous malignant melanoma is a life-threatening cancer with poor prognosis due to a high metastasis potential. The main obstacle in treatment of metastatic melanoma is the resistance to chemotherapy. Recent studies indicated that apoptosis is a common mechanism of action for various cytotoxic agents. As p53 plays an important part in apoptosis, we investigated the role of p53 in chemosensitivity of melanoma cells. Previously, we found that melanoma cell lines containing wild-type p53 have significantly higher response rates to chemotherapy than cell lines with a mutant p53 gene. To confirm the role of p53 in melanoma chemosensitivity further, we transfected an expression vector, pED1, which carries a mutant p53 gene, into a wild-type p53 melanoma cell line, MMAN. We examined the effect of mutant p53 on camptothecin-induced apoptosis and the expression of genes which are known to be involved in apoptosis or drug resistance, such as bcl-2, bax, bak, p21waf1, and P-glycoprotein. Our results indicate that overexpression of the mutant p53 increased the growth rate of MMAN cells, reduced the sensitivity to camptothecin, and lowered drug-induced apoptosis by 2-3-fold. Flow cytometry indicated that the camptothecin-induced apoptosis is not associated with G1 arrest. Furthermore, camptothecin treatment reduced bcl-2 and P-glycoprotein expression in wild-type p53 MMAN cells, but not cells overexpressing mutant p53. These results demonstrate that p53 mutational status is a determinant of melanoma chemosensitivity. p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.
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PMID:p53-dependent apoptosis in melanoma cells after treatment with camptothecin. 1069 11

The major limitation of treatment with antimetabolite drugs is that they produce resistant clones both in vitro and in patients who either do not respond to treatment or relapse soon after response has been documented. To better understand the phenomenon of cross-resistance, we developed seven CEM/ara-C-resistant leukemic clones from the CEM/0 (wt) cell line. These clones ranged from 4- to 3.5 x 10(8)-fold more resistant to ara-C than the wt CEM/0 cell line. Using this model, we determined IC50 concentrations to several chemotherapeutic agents and gamma radiation, and we also studied pro- (p53) and anti-apoptotic (bcl-2) proteins, as well as P-glycoprotein (P-gp) and multidrug resistance related protein (MRP). The cell viability assays showed that these clones were cross-resistant to 6-thioguanine (6-TG) or 6-mercaptoguanosine (6-TGuo) from 1.1- to 8.8-fold with ara-C; cross-resistance to vincristine (VCR) was from 200- to 1 x 10(4)-fold with ara-C. Taxotere (TXR) showed cross-resistance with ara-C from 1.39- to 3.03 x 10(3)-fold; dexamethasone (DEX) also showed a significant degree of cross-resistance from 27.4- to 3.87 x 10(7)-fold. Gamma radiation treatments from 0.77 Gy to 12.3 Gy showed a radiation dose-dependent cross-resistance with ara-C from 1.43- to 2.93-fold. Idarubicin was collaterally sensitive with ara-C from 4.6- to 1 x 10(9)-fold in these cell lines. The CEM/ara-C/G resistant cell line was 3-fold more sensitive to 6-TG or VCR than CEM/0 (wt), and 5-fold more sensitive to 6-TGuo. This cell clone expressed p53 and did not overexpress bcl-2 protein. All of the cell lines studied, CEM/0 (wt) and the ara-C resistant clones, showed functional p53 protein. The cell treatment with 0.1, 1 and 10 microM ara-C for 48 hours showed increased p53 protein expression in most of these lines. No increase in bcl-2 protein expression was seen in the wt cell line after ara-C treatment for 48 hours. Three cell lines resistant to ara-C (CEM/ara-C/B, CEM/ara-C/D and CEM/ara-C/I) showed an important increased expression of bcl-2 protein after treatment with 1 microM ara-C, but not after 10 microM. This alteration may lead to resistance to apoptosis and enhanced cell survival. The ratio of bcl-2 to p53 was increased significantly in these three clones, thus favoring an anti-apoptotic drive. All of the cell lines examined were negative for MRP expression and only two, CEM/ara-C/B and CEM/ara-C/J, were positive for MRP functional activity. However, three ara-C resistant cell clones, CEM/ara-C/7A, CEM/ara-C/B and CEM/ara-C/G, were positive for P-gp expression and functional activity. It is apparent that selection for ara-C resistance confers cross-resistance to many other classes of drugs and gamma radiation, probably due to bcl-2 protein overexpression or P-gp and MRP expression, as independent mechanisms.
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PMID:Cytosine arabinoside (ara-C) resistance confers cross-resistance or collateral sensitivity to other classes of anti-leukemic drugs. 1076 46

Preoperative chemotherapy administered to breast cancer (BC) patients is a model for studying in vivo the interaction between cytotoxic treatment and clinical and biological parameters. Apoptosis induced by anticancer agents is a mechanism of treatment activity; therefore, overexpression of genes inhibiting the apoptotic pathway could produce drug resistant tumors. In the present study, the two most studied inhibitors of apoptosis, the bcl-2 gene and the mutant p53, have been evaluated to assess whether they may play a role in modulating response of BC to primary chemotherapy. From August 1990 to January 1997, 143 patients bearing T(2-4)N(0-1)M0 primary BC were submitted to two different chemotherapeutic regimens before surgery. The first 64 received the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen (on days 1 and 8 and every 28 days thereafter) associated with tamoxifen (30 mg daily) in case of estrogen receptor (ER)-positive BC, and the remaining 79 were submitted to single agent epirubicin (120 mg/m2 every 21 days). The expression of p53, bcl-2, Ki67, ER, progesterone receptor, c-erbB2, and the multidrug resistance P-glycoprotein (gp-170) was evaluated in BC specimens obtained at diagnosis by incision biopsy and at postchemotherapy surgery. At the end of chemotherapy administration (median, 3 cycles; range, 2-6), the clinical complete response (cCR) rate was superimposable in the patient subgroups with bcl-2-positive or -negative primary tumors; conversely, p53 expression, at a cutoff of 10% positive cells, was significantly associated with a lower cCR rate (9.4 versus 27.0%; P < 0.04). p53 was a significant predictor for poor cCR in the subset submitted to epirubicin (3.6 versus 25.5%; P < 0.02; in patients with p53+ and p53- BC, respectively); by contrast, only a trend toward lower cCR has been observed in patients with p53+ tumors receiving CMF +/- tamoxifen with respect to p53- ones. The distribution of cCR according to the gp-170-positive or -negative tumors was 8 versus 22% in patients submitted to epirubicin and 29 versus 30% in those receiving CMF +/- tamoxifen, respectively. In a multivariate regression analysis, after adjusting for treatment administered (epirubicin versus CMF +/- tamoxifen), menopausal status, tumor and node status, histology grade, ER, progesterone receptor, c-erbB2, Ki67, bcl-2, and gp-170 expression, the p53 status maintained an independent predictive role for cCR. Most of the tumors undergoing change in percentage of p53 expression after both treatments originally harbored mutant protein, and only four BC specimens that were p53 negative before chemotherapy became positive afterward. These data confirm in vivo the concept that the responsiveness of tumors to chemotherapy in part derives from the capability of BC cells to undergo apoptosis. The role of mutated p53 in preventing response is more evident in patients submitted to epirubicin, and this may be caused by the up-regulation of multidrug resistance gene expression by p53 inactivation. p53 is a stable phenotype and is not inducible by at least three or four chemotherapy cycles.
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PMID:p53 but not bcl-2 immunostaining is predictive of poor clinical complete response to primary chemotherapy in breast cancer patients. 1091 20

Markers of anticancer drug resistance are predictive of treatment response and outcome in patients with acute myeloid leukemia. Immunologic detection of the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1), correlate with functional assays of drug resistance. These accumulation defects also appear operable in acute lymphoblastic leukemia. Many of the efflux pumps identified share significant structural homology with the large superfamily of ATP-binding cassette transporters. Other markers such as lung-resistance protein, bcl-2, and breast cancer-resistance protein, have been described in acute myeloid leukemia patients although their pathophysiology and clinical relevance are less clear and the methodology for their quantification are not well standardized. Preclinical studies have shown that small molecules capable of reversing efflux can restore drug sensitivity in resistant tumor models. Although initial clinical studies were limited by both potency and specificity of the reverser, later studies with more effective reversers have in many instances been limited by pharmacokinetic interactions exacerbating the clinical toxicities of chemotherapy. Although one large randomized study has demonstrated a proven survival advantage without increased toxicity using cyclosporine, the inconsistent results with other modulators raise doubt as to the utility and overall strategy of using drug efflux blockers in patients with established Pgp overexpression. Many of these patients have additional resistance mechanisms, and achieving meaningful clinical responses will likely require more complex clinical strategies. Preventing or delaying development of drug resistance in chemosensitive patients represents another therapeutic strategy to be tested.
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PMID:Drug resistance mechanisms in acute leukemia. 1114 81

Flavopiridol inhibits phosphokinases. Its activity is strongest on cyclin dependent kinases (cdk-1, -2, -4, -6, -7) and less on receptor tyrosine kinases (EGFR), receptor associates tyrosine kinases (pp60 Src) and on signal transducing kinases (PKC and Erk-1). Although the inhibiting activity of flavopiridol is strongest for cdk, the cytotoxic activity of flavopiridol is not limited to cycling cells. Resting cells are also killed. This fact suggests that inhibition of cdks involved in the control of cell cycle is not the only mechanism of action. Inhibition of cdk's with additional functions (i.e. involved in the control of transcription or function of proteins that do not control cell cycle) may contribute to the antitumoral effect. Moreover, direct and indirect inhibition of receptor activation (EGFR) and/or a direct inhibition of kinases (pp60 Src, PKC, Erk-1) involved in the signal transduction pathway could play a role in the antiproliferative activity of flavopiridol. From pharmacokinetic data in patients it can be concluded that the inhibitory activity (IC50) of flavopiridol on these kinases is in the range of concentrations that might be achieved intracellularly after systemic application of non-toxic doses of flavopiridol. However, no in situ data from flavopiridol treated cells have been published yet that prove that by inhibition of EGFR, pp60 Src, PKC and/or Erk-1 (in addition to inhibition of cdk's) flavopiridol is able to induce apoptosis. Thus many questions regarding the detailed mechanism of antitumoral action of flavopiridol are still open. For the design of protocols for future clinical studies this review covers the essential information available on the mechanism of antitumoral activity of flavopiridol. The characteristics of this antitumoral activity include: High rate of apoptosis, especially in leukemic cells; synergy with the antitumoral activity of many cytostatics; independence of its efficacy on pRb, p53 and Bcl-2 expression; lack of interference with the most frequent multidrug resistance proteins (P-glycoprotein and MRP-190); and a strong antiangiogenic activity. Based on these pharmacological data it can be concluded that flavopiridol could be therapeutically active in tumor patients: independent on the genetic status of their tumors or leukemias (i.e. mutations of the pRb and/or p53, amplification of bcl-2); in spite of drug resistance of their tumors induced by first line treatment (and caused by enhanced expression of multidrug resistance proteins); in combination with conventional chemotherapeutics preferentially given prior to flavopiridol; and due to a complex mechanism involving cytotoxicity on cycling and on resting tumor cells, apoptosis and antiangiogenic activity. In consequence, flavopiridol is a highly attractive, new antitumoral compound and deserves further elucidation of its clinical potency.
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PMID:Mechanisms of action of flavopiridol. 1131 60

Fas and Fas ligand (FasL) mediate T-lymphocyte cytotoxicity and may also induce physiologic apoptosis in breast epithelium associated with menstruation and cessation of lactation. Altered expression may thus be associated with breast carcinoma progression, chemotherapy response, or outcome. We performed a clinicopathologic analysis of immunohistochemical staining for Fas and FasL, as well as bax, bcl-2, glutathione-s-transferase, HER-2 (c-erbB-2), Ki67, P-glycoprotein, p53, and hormone receptors in pretreatment breast biopsies from 34 patients with locally advanced or limited stage IV breast carcinoma who received preoperative (neoadjuvant, primary) chemotherapy followed by lumpectomy or mastectomy. Neoplastic cells expressed Fas in 44% and FasL in 85% of pretreatment biopsies. Fas immunostaining was more frequent in tumors with larger size (p = 0.02) and pretreatment metastases (p = 0.03). Combined Fas and p53 staining correlated with pathologic complete response (4 of 5 CR versus 6 of 29 other, p = 0.02), as did combined p53 and lack of FasL staining (2 of 5 CR versus 0 of 29 other, p = 0.02), but individually Fas, p53, and lack of FasL immunostaining demonstrated only trends to correlation with CR (p = 0.13-0.15). No other biomarkers correlated with chemotherapeutic response. Neither FasL nor Fas expression was associated with the degree of peritumoral lymphocytic infiltration, or with expression of the other biomarkers. Recurrence was more frequent in Fas-expressing tumors (recurrent cases 7 of 10 Fas positive versus nonrecurrent 8 of 24 Fas positive, p = 0.07). In this patient group, Fas expression is associated with aggressive tumor behavior. Biomarker immunostaining correlates weakly with pathologic response to preoperative chemotherapy, in keeping with complex or heterogeneous tumor-drug interactions.
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PMID:Clinicopathologic Analysis of Fas, Fas Ligand, and Other Biomarkers in Locally Advanced Breast Carcinoma. 1134 71


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