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P-gp
P-gp
P-gp(4)

P-gp, or multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1), is a transmembrane glycoprotein which pumps many foreign substances out of cells.(1, 2) P-gp is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum.(2) P-gp is expressed in the intestinal epithelium where it pumps toxins or drugs back into the intestinal lumen, in liver cells where it pumps them into bile ducts, in the cells of the proximal tubular of the kidney where it pumps them into urine-conducting ducts, and in the capillary endothelial cells comprising the blood-brain barrier and blood-testis barrier, where it pumps them back into the capillaries.(2) P-gp's ability to transport the substrates accounts for the many roles of P-gp including: regulating the distribution and bioavailability of drugs, increased intestinal expression of P-gp can reduce the absorption of drugs that are substrates for P-gp, active cellular transport of antineoplastics resulting in multidrug resistance to these drugs, the removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen, and the transport of compounds out of the brain across the blood-brain barrier.(1, 2)
The N-terminal half of the molecule contains 6 transmembrane domains, followed by a large cytoplasmic domain with an ATP-binding site, and then a second section with 6 transmembrane domains and an ATP-binding site.(2)
Some cancer cells express large amounts of P-gp, which renders these cancers multi-drug resistant.(2,3)

Drugs/Indications
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
OCZ103-OS Oncozyme P2: NSCLC, CRC trials
bivatuzumab BIWA Korea Otsuka; Boehringer Ingelheim P1: HNN, NSCLC, BC, squamous, adenocarcinoma, HCC (2013) trials
RO5429083 Roche P1: AML, solid trials
Failed Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
tariquidar XR9576 QLT Last trial started in for oncology 2003; P3: NSCLC (terminated); P2: adrenal; P1: brain, Ewing's, BC, lung, ovarian trials
zosuquidar LY335979 Kanisa, Eli Lilly Last new trial 2005; P3: leukemia, myelodysplastic syndrome trials
PSC 833 noncorporate Last trial started in 2005; P2: BC; P3: leukemia; P1: RCC, lymphoma, solid trials


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References

1. Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. Journal of lipid research. 2001;42(7):1007-17.

2. P-glycoprotein [cited]; Available from: http://en.wikipedia.org/wiki/P-glycoprotein

3. Drug Delivery in Oncology: From Basic Research to Cancer Therapy 2011.

4. Juranka P, Zastawny R, Ling V. P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. The FASEB Journal. 1989;3(14):2583-92.



News
Thursday, September 15, 2016 11:42 PM|Xianlong Ling, Yuan Zhou, Shi-Wei Li, Bin Yan, Lei Wen|International Journal of Biological Sciences|Labels: electron transport, P-gp, liver cancer

Multidrug resistance (MDR) is a critical problem in the chemotherapy of cancers. Human hepatocellular carcinoma (HCC) responds poorly to chemotherapy owing to its potent MDR. Chemotherapeutic drugs primarily act by inducing apoptosis of cancer cells, and defects in apoptosis may result in MDR. Mitochondrial permeability transition (mPT) is implicated as an important event in the control of cell death or survival and mPT represents a target for the development of cytotoxic drugs. This study aimed to investigate the effects of selective opener (Atractyloside glycoside, ATR) and inhibitor (Cyclosporine A, CsA) of mitochondrial permeability transition pore (mPTP) on a CDDP-resistant HCC cell line (SK-Hep1 cells). In this study, a stable MDR phenotype characterization of SK-Hep1 cell line (SK-Hep1/CDDP cells) was established and used to investigate the role of mPTP in MDR. Results suggested that ATR accelerated the decrease of mitochondrial membrane potential (ΔΨm), reduced the Bax activity, and increased the apoptosis of SK-Hep1/CDDP cells; while CsA inhibited mPTP opening, reduced and delayed the decline of mitochondrial membrane potential, and increased the Bax activity, leading to increased tolerance of SK-Hep1/CDDP cells to apoptosis induction. However, mPTP activity had no effect on the expression of MDR1 in cells,meanwhile the P-gp translocation to mitochondria was increased, and functionally activated. In conclusion, selective modulation of mPTP can affect MDR in human HCC cells. Therefore, activation of mPTP may provide a new strategy to sensitize cancer cells to chemotherapeutic drugs and to reverse the MDR in cancer cells.

Tuesday, September 13, 2016 8:19 PM|K. Trumpi, B.L. Emmink, A.M. Prins, M.G.H. van Oijen, P.J. van Diest, C.J.A. Punt, M. Koopman, O. Kranenburg, I.H.M. Borel Rinkes|Journal of Cancer (RSS 2.0)|Labels: P-gp, CRC

Background: Active efflux of irinotecan by ATP-binding cassette (ABC)-transporters, in particular ABCB1 and ABCG2, is a well-established drug resistance mechanism in vitro and in pre-clinical mouse models, but its relevance in colorectal cancer (CRC) patients is unknown. Therefore, we assessed the association between ABC-transporter expression and tumour response to irinotecan in patients with metastatic CRC.

Methods: Tissue microarrays of a large cohort of metastatic CRC patients treated with irinotecan in a prospective study (CAIRO study; n=566) were analysed for expression of ABCB1 and ABCG2 by immunohistochemistry. Kaplan-Meier and Cox proportional hazard regression analyses were performed to assess the association of ABC transporter expression with irinotecan response. Gene expression profiles of 17 paired tumours were used to assess the concordance of ABCB1/ABCG2 expression in primary CRC and corresponding metastases.

Results: The response to irinotecan was not significantly different between primary tumours with positive versus negative expression of ABCB1 (5.8 vs 5.7 months, p=0.696) or ABCG2 (5.7 vs 6.1 months, p=0.811). Multivariate analysis showed neither ABCB1 nor ABCG2 were independent predictors for progression free survival. There was a mediocre to poor concordance between ABC-transporter expression in paired tumours.

Conclusion: In metastatic CRC, ABC-transporter expression in the primary tumour does not predict irinotecan response.

Friday, August 5, 2016 9:30 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: P-gp, CML
Early evaluation of ABCB1 mRNA expression may help identify CML patients who are likely to be resistant to first- and second-generation tyrosine kinase inhibitors.
Tuesday, July 19, 2016 9:22 AM|Wang, W.-J., Li, C.-F., Chu, Y.-Y., Wang, Y.-H., Hour, T.-C., Yen, C.-J., Chang, W.-C., Wang, J.-M.|Clinical Cancer Research Online First Articles|Labels: EGFR, P-gp, STAT, bladder cancer

Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel (PTX) for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with PTX, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy. Experimental Design: Loss-of-function assays were performed to elucidate the role of the epidermal growth factor receptor (EGFR) and transducer and activator of transcription 3 (STAT3) in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and PTX sensitivity. Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and PTX. Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and PTX by combination with either gefitinib or S3I-201.

Tuesday, June 21, 2016 4:20 AM|Saundra S. Buys, Deborah Fletcher, Roberta Melis, Kamisha L. Johnson‐Davis, Elaine Lyon, Elisabeth M. Malmberg, Gwendolyn A. McMillin|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: P-gp, breast cancer

Multi‐gene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19 and ABCB1
Jennifer L. Powers Saundra S. Buys, Deborah Fletcher, Roberta Melis, Kamisha L. Johnson‐Davis, Elaine Lyon, Elisabeth M. Malmberg, Gwendolyn A. McMillin
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. -
Tamoxifen is metabolically activated to 4‐hydroxytamoxifen and endoxifen by cytochrome P450 (CYP). CYP phenotypes have been correlated to tamoxifen outcomes, but few have considered drug interactions or combinations of genes. Fewer still have considered ABCB1, which encodes P‐glycoprotein and transports active tamoxifen metabolites. We compared the concentrations of tamoxifen and metabolites in 116 breast cancer patients with predicted phenotypes for CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19 and ABCB1 genotypes. A significant correlation between CYP2D6 phenotypes and tamoxifen metabolites was seen, strongest for endoxifen (p<0.0001). Statistical fit of the data improved when using gene activity scores adjusted for known drug interactions. Concentration of tamoxifen was significantly higher (p = 0.02) for patients taking a CYP2C19 inhibitor. No significant relationships were found for other genes unless patients were subgrouped according to CYP2D6 phenotypes or ABCB1 genotypes. Lower concentrations of endoxifen and endoxifen/4‐hydroxytamoxifen ratios were seen with impaired CYP2C9 (p = 0.05 and 0.03, respectively) if patients had the same CYP2D6 phenotype and were not taking a CYP2D6 or CYP2C19 inhibitor. Lower concentrations of 4‐hydroxytamoxifen were seen for impaired CYP2C19 when ABCB1 SNP3435 was nonvariant (p = 0.04). With three impaired CYP phenotypes, endoxifen concentrations were lower than if only CYP2D6 was impaired (p = 0.05). When CYP2D6 was impaired, ABCB1 3435 CC (rs1045642) was associated with significantly higher endoxifen (p = 0.03). Thus, impairment in CYP2C9, CYP2C19, or ABCB1 contributes to a lower steady‐state endoxifen concentration at the dose studied. These studies represent an improved way of examining relationships between pharmacogenetics, drug concentrations, and clinical outcomes and warrants study in larger populations. This article is protected by copyright. All rights reserved

Tuesday, February 23, 2016 5:00 PM|Walter Haefeli|Pharmaceutics|Labels: Bcl-2, P-gp, lymphoma
Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug–drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug–drug interactions.
Thursday, February 4, 2016 1:34 AM|Pharmacogenetics and Genomics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: HIF, P-gp, lung cancer
Conclusion: This study showed that the SLCO1B3 c.699 G>A polymorphism may predict anemia and ABCB1, HIF1A polymorphism are highly predictive for worse survival in advanced NSCLC with first-line paclitaxel and carboplatin. (Source: Pharmacogenetics and Genomics)

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