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:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Higher technetium-99m methoxyisobutylisonitrile (MIBI) uptake in non-small cell lung cancer (NSCLC) has been reported to be associated with a positive response to chemotherapy. It has previously been found that in tumour cells, P-glycoprotein (Pgp) expression is of importance for tracer uptake. However, some studies have indicated that Pgp expression does not play an important role in (99m)Tc-MIBI uptake in NSCLC; indeed, a negative correlation between (99m)Tc-MIBI uptake and Pgp expression has been reported. Against the background of conflicting results, our aim was to evaluate the relationship between (99m)Tc-MIBI uptake, prognosis and Pgp expression in NSCLC. A total of 37 patients with NSCLC underwent (99m)Tc-MIBI single-photon emission tomography (SPET) before chemotherapy. In 19 patients both Pgp and p53 expression, and in two patients only p53 expression (due to the limited biopsy material), were measured with immunohistochemical staining. (99m)Tc-MIBI uptake was significantly higher in responders than in non-responders: 3.09+/-1.14 vs 2.24+/-0.88 ( P<0.03) and 3.09+/-1.08 vs 2.37+/-1.06 ( P<0.05) for the early ratio (ER) and the delayed ratio (DR), respectively. The wash-out rate (WR) of responders was not significantly different from that of non-responders. We found no significant differences in ER, DR and WR among the groups positive or negative for Pgp and p53 status. There was a significant positive correlation between the survival rate and both ER and DR: r=0.49 ( P=0.003) and r=0.40 ( P=0.018), respectively. Patients with ER and DR values above 3 showed significantly longer survival than those with values below 3: 14.7+/-8.5 months vs 7.3+/-5.1 months ( P<0.009) and 13.2+/-8.4 months vs 7.4+/-5.3 months ( P<0.04) for ER and DR, respectively. However, interestingly, and in contrast to expectations, patients with a Pgp score of +2 showed significantly longer survival (12.9+/-6.7 months) than those with Pgp scores of +1 (4.4+/-3.0 months) or - (negative) (3.8+/-2.2 months) ( P<0.009 and P<0.02, respectively). Our results suggest that in NSCLC, patients with higher (99m)Tc-MIBI uptake tend to show a positive response to chemotherapy, and patients with ER and DR values above 3 have a significantly better prognosis. We also found that Pgp expression seems to play only a minor role in (99m)Tc-MIBI uptake. Our finding that patients with ER and DR values above 3 have a better prognosis needs to be confirmed in larger series of patients.
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PMID:99mTc-MIBI SPET in non-small cell lung cancer in relationship with Pgp and prognosis. 1211 Nov 27

RLIP76 functions as an ATP-dependent transporter of amphiphilic chemotherapeutic drugs such as doxorubicin (DOX, adriamycin), as well as of glutathione-conjugates of endogenous electrophilic toxins such as 4-hydroxynonenal (4HNE). RLIP76 couples transport and ATP-hydrolysis with a 1:1 stoichiometry, making the ATPase activity of RLIP76 an excellent surrogate for its transport activity. Present studies were performed to determine the relationship of the RLIP76 ATPase activity with DOX and 4HNE resistance in a panel of 13 native human lung cancer cell lines. RLIP76 was purified from each cell line and homogeneity demonstrated by SDS-PAGE and amino acid composition analysis. Anti-RLIP76 antibodies were shown by Ouchterlony double immunodiffusion tests to be non-cross-reactive with any other proteins including P-glycoprotein (Pgp) or multidrug resistance associated protein (MRP). These antibodies completely immunoprecipitated ATPase activity of purified RLIP76 fractions, further confirming homogeneity of purified RLIP76. RLIP76 ATPase purified from NSCLC cell lines was about 2-fold more active than that from SCLC in the absence of the stimulator dinitrophenyl S-glutathione (206+/-47, n=7 vs. 94+/-22, n=6, nmol/min/mg protein, respectively), or in its presence (340+/-60, n=7 vs. 186+/-32, n=6, nmol/min/mg; p<0.01). Partial tryptic digest revealed a 44 kDa internal fragment of RLIP76 beginning at Thr-294 in NSCLC cell lines. This fragment was absent from all SCLC, suggesting the possibility that the activity of RLIP76 in SCLC and NSCLC is differentially regulated through post-translational modifications. Taken together, these findings suggest that RLIP76 activity is a general determinant of 4HNE and DOX resistance, and that its activity contributes to the drug-resistant phenotype of NSCLC.
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PMID:Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells. 1252 36

In vitro studies have shown that technetium-99m tetrofosmin (Tc-99m TF) is a transport substrate for the P-glycoprotein (Pgp) pump. Therefore, Tc-99m TF uptake of tumors can be used to predict chemotherapy response in lung cancers. However, whether lung resistance-related protein (LRP) expression affects tumor accumulation and efflux of Tc-99m TF in lung cancers is not known. Our aim was to use Tc-99m TF uptake of tumors to predict paclitaxel-based chemotherapy response of non-small cell lung cancer (NSCLC) and to compare Pgp or LRP expression. Twenty patients with advanced NSCLC received Tc-99m TF chest images before Taxol-based chemotherapy was used in this study. The chemotherapy response was evaluated by clinical and radiological methods in the third month after completion of treatment. No significant differences of prognostic factors (age, sex, body weight loss, performance status, tumor size, tumor stage, and tumor cell type) were found between the patients with good and those with poor responses. Early and delayed tumor/normal lung (T/L) uptake ratios were calculated on Tc-99m TF chest images. Immunohistochemical analyses were performed on multiple nonconsecutive sections of the biopsy specimens to detect Pgp and LPR expressions. The early and delayed T/L uptake ratios of 10 patients with good response were significantly higher than those of the other 10 patients with poor response. Significantly higher early and delayed T/L uptake ratios were found in patients with negative than those with positive Pgp expression ( p < 0.05). However, no significant differences of early and delayed T/L uptake ratios were found between patients with negative and positive LRP expressions ( p > 0.05). We found that Tc-99m TF imaging could accurately predict Taxol-base chemotherapy response. In addition, the Tc-99m TF tumor uptake was related to Pgp but not LPR expression in NSCLC.
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PMID:Using technetium-99m tetrofosmin chest imaging to predict taxol-based chemotherapy response in non-small cell lung cancer but not related to lung resistance protein expression. 1295 49

In vitro studies have shown that technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) is a transport substrate for the P-glycoprotein (Pgp) pump. Therefore, Tc-99m MIBI uptake of tumors can be used to predict chemotherapy response in lung cancers. However, whether lung resistance-related protein (LRP) expression affects tumor accumulation and efflux of Tc-99m MIBI in lung cancers is not known. Our aim was to use Tc-99m MIBI uptake of tumors to predict Taxol based chemotherapy response of advanced non-small cell lung cancer (NSCLC) and to compare Pgp or LRP expression. Before chemotherapy with Taxol, 30 patients with stage IIIb or IV NSCLC were enrolled in this study. Chemotherapy response was evaluated in the third month after completion of treatment by clinical and radiological methods. No significant differences were found for other prognostic factors (age, sex, body weight loss, performance status, tumor cell type, and tumor stage) between the 15 patients with good response and the other 15 patients with poor response. Early chest single photon emission computed tomography (SPECT) was performed 10 min after intravenous injection of Tc-99m MIBI. Early tumor-to-normal lung (T/L) uptake ratios were calculated quantitatively on Tc-99m MIBI chest SPECT images. Immunohistochemical analyses were performed on multiple nonconsecutive sections of the biopsy specimens to determine Pgp and LRP expressions. The T/L uptake ratios on early Tc-99m MIBI chest SPECT images of 15 patients with good response were significantly higher than those of the other 15 patients with poor response. Significantly higher T/L uptake ratios were found in patients with negative than positive Pgp expression (p<0.05). However, no significant differences of T/L uptake ratios were found between patients with negative and positive LRP expressions (p>0.05). We concluded that Tc-99m MIBI chest SPECT could accurately predict Taxol base chemotherapy response of patients with advanced NSCLC. In addition, The Tc-99m MIBI tumor uptake was related to Pgp but not LPR expression in NSCLC.
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PMID:Usefulness of chest single photon emission computed tomography with technetium-99m methoxyisobutylisonitrile to predict taxol based chemotherapy response in advanced non-small cell lung cancer. 1296 29

Our aim was to compare Taxol-based chemotherapy response of non-small cell lung cancer (NSCLC) with P-glycoprotein (Pgp) or lung resistance protein expression (LRP). Immunohistochemical analyses were performed on multiple nonconsecutive sections of the biopsy specimens to detect Pgp and LPR expressions in 40 patients with advanced NSCLC before Taxol-based chemotherapy. The chemotherapy response was evaluated by clinical and radiological methods in the third month after completion of treatment. No significant differences of prognostic factors (age, sex, body weight loss, performance status, tumor size, tumor stage, and tumor cell type) were found between the 20 patients with good and the 20 patients with poor responses. The incidence difference of positive Pgp expressions between good and poor responses was significant, however, the difference of LRP expression was not. We concluded that Taxol-based chemotherapy response of patients with NSCLC was related to Pgp but not LPR expression.
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PMID:Comparing the relationship of Taxol-based chemotherapy response with P-glycoprotein and lung resistance-related protein expression in non-small cell lung cancer. 1470 70

Taxanes (docetaxel and paclitaxel) as well as cisplatin (CDDP) are key chemotherapeutic agents in the treatment of non-small cell lung cancer (NSCLC). Although some indicators of taxane resistance, such as beta-tubulin mutations, P-glycoprotein (P-gp) and Bcl-2, have been reported in malignant cells, the mechanisms of taxane resistance in NSCLCs have yet to be fully elucidated. We evaluated in vitro chemosensitivity to docetaxel (DOC) and CDDP in 87 surgically-resected specimens of NSCLC by collagen gel-droplet embedded culture drug sensitivity test (CD-DST). Bcl-2 and P-gp expression in these specimens were also investigated by immunohistochemistry. We examined the association between Bcl-2 and P-gp expression and in vitro chemosensitivity to DOC and CDDP. Out of the 87 NSCLCs that were examined, Bcl-2 and P-gp were expressed in 32 (36.8%) and 28 (32.2%) of the tumors, respectively. Positive Bcl-2 expression was significantly associated with enhanced DOC sensitivity in NSCLCs (p=0.007) while no apparent association was observed between DOC sensitivity and P-gp expression. Interestingly, although DOC, but not CDDP has been reported to be a substrate of P-gp, P-gp expression was significantly inversely correlated with CDDP sensitivity in pulmonary adenocarcinomas (p=0.03). Positive Bcl-2 expression may be a promising indicator in determining in vitro taxane sensitivity in NSCLCs. On the other hand, positive P-gp expression may be an indicator of enhanced in vitro resistance to CDDP in pulmonary adenocarcinomas.
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PMID:Bcl-2 overexpression enhances in vitro sensitivity against docetaxel in non-small cell lung cancer. 1564 8

In order to understand and overcome multidrug resistance (MDR) of human non-small cell lung cancer (NSCLC), mRNA and protein expression levels of P-glycoprotein (MDR1), multidrug resistance-associated protein 1 (MRP1), and lung resistance-related protein (LRP) were investigated and compared with the chemosensitivity and the intracellular/intranuclear cisplatin accumulation of three NSCLC cell lines (Ma-10, Ma-31, and Ma-46). Ma-31 was more resistant than Ma-10 and Ma-46 to cisplatin, carboplatin, etoposide, and paclitaxel. The mRNA level of MDR1 was extremely low, and MDR1 protein was not detected in all cell lines. MRP1 mRNA expression was highest in Ma-31 and lowest in Ma-10, but there was no notable difference between the MRP1 protein expression in three cell lines. LRP mRNA/protein was equally expressed in Ma-10 and Ma-31, but was nominal in Ma-46. The intracellular/intranuclear cisplatin accumulation of the cells was determined to be Ma-31>Ma-46>Ma-10. Thus, MDR1, MRP1, and LRP mRNA and protein expression levels were not correlated with the chemosensitivity or the intracellular/intranuclear cisplatin accumulation of each cell line. The present results indicate that MDR proteins (MDR1, MRP1, and LRP) may not play an important role in the chemoresistance and drug efflux of NSCLC cells.
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PMID:Expression of multidrug resistance proteins and accumulation of cisplatin in human non-small cell lung cancer cells. 1580 14

Breast cancer resistance protein (BCRP, ABCG2) is a recently identified member of the ATP-binding cassette family of cell surface transport proteins. This study was conducted to investigate the effect of a series of newly synthesized 1,4-dihydropyridines and pyridines, designed as potent P-glycoprotein inhibitors, on BCRP-mediated drug efflux both in vitro and in vivo. The effects of 25 synthesized dihydropyridines and corresponding pyridines along with 4 commercially available dihydropyridines (niguldipine, nicardipine, nifedipine, and nitrendipine) on the intracellular accumulation of the BCRP substrate mitoxantrone were evaluated in BCRP-expressing human breast cancer MCF-7/MX100 and human non-small cell lung cancer H460/MX20 cells. At a 2.5 microM concentration, 24 of 25 newly synthesized dihydropyridines and pyridines produced a significant increase of mitoxantrone accumulation in both cell lines. The most potent compound was able to enhance mitoxantrone accumulation approximately 4.5-fold, greater than that obtained with 10 microM fumitremorgin C, which is a specific BCRP inhibitor. The results from the two cell lines showed good correlation (r(2) = 0.71, p < 0.01). Niguldipine, nicardipine, and nitrendipine also demonstrated potent BCRP inhibition, whereas nifedipine had no effect. The effects of the dihydropyridine and pyridine compounds on mitoxantrone cytotoxicity paralleled their effects on mitoxantrone accumulation. Coadministration of a selected dihydropyridine compound, I(m) [DHP-014; 3-(3-(4,4-diphenylpiperidin-1-yl)propyl) 5-methyl 4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate)] with topotecan, a good BCRP substrate and a moderate to poor P-glycoprotein substrate, resulted in significant increases in the systemic exposure and peak concentration of topotecan in Sprague-Dawley rats when oral topotecan (2 mg/kg) was combined with 20 mg/kg DHP-014. The observed increase of topotecan exposure provides proof-of-concept for in vivo inhibition of BCRP by these agents.
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PMID:Effects of dihydropyridines and pyridines on multidrug resistance mediated by breast cancer resistance protein: in vitro and in vivo studies. 1590 73

Docetaxel belongs to the class of taxane antineoplastic agents that act by inducing microtubular stability and disrupting the dynamics of the microtubular network. The drug has shown a broad spectrum of antitumour activity in preclinical models as well as clinically, with responses observed in various disease types, including advanced breast cancer and non-small cell lung cancer. The pharmacokinetics and metabolism of docetaxel are extremely complex and have been the subject of intensive investigation in recent years. Docetaxel is subject to extensive metabolic conversion by the cytochrome P450 (CYP) 3A isoenzymes, which results in several pharmacologically inactive oxidation products. Elimination routes of docetaxel are also dependent on the presence of drug-transporting proteins, notably P-glycoprotein, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, impact substantially on interindividual variability in drug handling. Strategies to individualise docetaxel administration schedules based on phenotypic or genotype-dependent differences in CYP3A expression are underway and may ultimately lead to more selective chemotherapeutic use of this agent.
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PMID:Clinical pharmacokinetics of docetaxel : recent developments. 1650 58

Microtubules are crucial targets for cancer chemotherapeutic drugs, and new microtubule-directed agents are of continued interest in drug development. A novel microtubule-directed agent, ethyl-2-[N-rho-chlorobenzyl-(2'-methoxy)]-anilino-4-oxo -4, 5-dihydro-furan-3-carboxylate, was identified. The compound, designated K2154, inhibited cell proliferation, with IC(50) values of 10.3, 15.3, 9.6, 11.2, 12.8 and 12.1 muM in prostate cancer PC-3, hepatocellular carcinoma Hep3B, non-small cell lung cancer A549, colorectal cancer HT29 and HCT116, and P-glycoprotein-rich breast cancer NCI/ADR-RES cells, respectively. Because NCI/ADR-RES cells were susceptible to inhibition by K2154, it indicated that this compound is a poor substrate for P-glycoprotein. In this study, PC-3 cells were used to identify the anticancer mechanisms of K2154. K2154 induced an arrest of the cell cycle at G2/M phase and a subsequent increase of hypodiploid phase in PC-3 cells, whereas it only induced a moderate level of G2/M arrest with little increase of hypodiploid phase in normal prostate cells. K2154 inhibited microtubule assembly in both in vitro turbidity assay and in vivo microtubule spin-down experiment. Immunochemical examination showed that K2154 caused formation of abnormal mitotic characteristics with bipolar spindles, particularly, in beta(II)- and beta(III)-tubulin staining. It also induced several pathways, including cyclin B1 up-regulation, dephosphorylation on Tyr(15) and phosphorylation on Thr(161) of Cdk1 and Cdc25C phosphorylation, and roscovitine (a Cdk1 inhibitor) significantly inhibited K2154-induced apoptosis, suggesting a pro-apoptotic role of Cdk1. Phosphorylation of Bcl-2 and Bcl-xL and cleavage of Mcl-1, together with activation of caspase-9 and -3, indicated that mitochondrial pathway played a central role in K2154-mediated apoptotic cell death. Additionally, AIF contributed to a late phase of K2154-induced apoptotic pathway. In conclusion, it is suggested that K2154 displays an anticancer activity through a target on microtubules and a subsequent signaling cascade on cell cycle regulation and apoptotic machinery.
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PMID:Investigation of anti-tumor mechanisms of K2154: characterization of tubulin isotypes, mitotic arrest and apoptotic machinery. 1710 38


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