scholarly journals Transport Characteristics of Tryptanthrin and its Inhibitory Effect on P-gp and MRP2 in Caco-2 Cells

2011 ◽  
Vol 14 (3) ◽  
pp. 325 ◽  
Author(s):  
Xingang Zhu ◽  
Xuelian Zhang ◽  
Guo Ma ◽  
Junkai Yan ◽  
Honghai Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Intestinal Transport ◽  
Inhibitory Effect ◽  
Potential Influence ◽  
Preclinical Development ◽  
Efflux Transport ◽  
Apparent Permeability ◽  
Glycoprotein P ◽  
Pravastatin Sodium ◽  
P Glycoprotein

Purpose. Tryptanthrin, an indole quinazoline alkaloid with multiple medical activities, has been recently under preclinical development as an anti-tuberculosis and anti-tumor drug. The aims of this study are to characterize the intestinal transport of tryptanthrin in Caco-2 cells, to determine whether P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) are involved in this issue, and to evaluate the potential influence of tryptanthrin on the function of P-gp and MRP2. Methods. Transport assays of tryptanthrin were performed in Caco-2 monolayers with or without the supplement of P-gp and MRP2 inhibitors. Transport assays of P-gp and MRP2 substrates were also performed in the presence of tryptanthrin. The effect of tryptanthrin on the expression of P-gp and MRP2 was analyzed by reverse transcriptase-PCR. Results. Both absorption and secretion of tryptanthrin were concentration-independent at a low concentration range of 0.8–20 µM. The apparent permeability (Papp) for the apical (AP) to basolateral (BL) was 6.138 ± 0.291 × 10-5. The ratio of Papp (BL→AP) to Papp (AP→BL) was 0.77, suggesting greater permeability in the absorptive direction. Both the P-gp inhibitor, verapamil, and the MRP2 inhibitor, glibenclamide, didn’t affect the efflux transport of tryptanthrin. The efflux transport of the P-gp substrate, digoxin, and the MRP2 substrate, pravastatin sodium, decreased when tryptanthrin was present. However, tryptanthrin didn’t change the expression of P-gp and MRP2. Conclusions. Tryptanthrin was well absorbed across the Caco-2 monolayers, and its transepithelial transports were dominated by passive diffusion. Tryptanthrin was not a substrate, but a potential inhibitor of P-gp and MRP2. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Inhibitory Effect of Berberine on Broiler P-glycoprotein Expression and Function: In Situ and In Vitro Studies

2019 ◽  
Vol 20 (8) ◽  
pp. 1966 ◽  
Author(s):  
Yujuan Zhang ◽  
Li Guo ◽  
Jinhu Huang ◽  
Yong Sun ◽  
Fang He ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Effect ◽  
In Vitro Models ◽  
Apparent Permeability ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
And Function ◽  
Xenobiotic Receptor

Overcoming P-glycoprotein (P-gp) efflux is a strategy to improve the absorption and pharmacokinetics of its substrate drugs. Berberine inhibits P-gp and thereby increases the bioavailability of the P-gp substrate digoxin in rodents. However, the effects of berberine on P-gp in chickens are still unclear. Here, we studied the role of berberine in modulating broilers P-gp expression and function through both in situ and in vitro models. In addition, molecular docking was applied to analyze the interactions of berberine with P-gp as well as with chicken xenobiotic receptor (CXR). The results showed that the mRNA expression levels of chicken P-gp and CXR decreased in the ileum following exposure to berberine. The absorption rate constant of rhodamine 123 increased after berberine treatment, as detected using an in situ single-pass intestinal perfusion model. Efflux ratios of P-gp substrates (tilmicosin, ciprofloxacin, clindamycin, ampicillin, and enrofloxacin) decreased and the apparent permeability coefficients increased after co-incubation with berberine in MDCK-chAbcb1 cell models. Bidirectional assay results showed that berberine could be transported by chicken P-gp with a transport ratio of 4.20, and this was attenuated by verapamil (an inhibitor of P-gp), which resulted in a ratio of 1.13. Molecular docking revealed that berberine could form favorable interactions with the binding pockets of both CXR and P-gp, with docking scores of −7.8 and −9.5 kcal/mol, respectively. These results indicate that berberine is a substrate of chicken P-gp and down-regulates P-gp expression in chicken tissues, thereby increasing the absorption of P-gp substrates. Our findings suggest that berberine increases the bioavailability of other drugs and that drug-drug interactions should be considered when it is co-administered with other P-gp substrates with narrow therapeutic windows.

scholarly journals Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

2019 ◽  
Vol 442 ◽  
pp. 91-103 ◽  
Author(s):  
Albert A. De Vera ◽  
Pranav Gupta ◽  
Zining Lei ◽  
Dan Liao ◽  
Silpa Narayanan ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein

scholarly journals Extract from Dioscorea bulbifera L. rhizomes aggravate pirarubicin-induced cardiotoxicity by inhibiting the expression of P-glycoprotein and multidrug resistance-associated protein 2 in the mouse liver

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Li-rui Sun ◽  
Qiu-shi Guo ◽  
Wei Zhou ◽  
Min Li
Keyword(s):  
Multidrug Resistance ◽  
Mouse Liver ◽  
Adverse Reactions ◽  
Heart Tissue ◽  
Efflux Transporters ◽  
Glycoprotein P ◽  
Chinese Herbal ◽  
Good Safety Profile ◽  
P Glycoprotein ◽  
Dioscorea Bulbifera

AbstractChinese herbal medicine is widely used because it has a good safety profile and few side effects. However, the risk of adverse drug reactions caused by herb-drug interactions (HDIs) is often overlooked. Therefore, the task of identifying possible HDIs and elucidating their mechanisms is of great significance for the prevention and treatment of HDI-related adverse reactions. Since extract from Dioscorea bulbifera L. rhizomes (DB) can cause various degrees of liver damage, it is speculated that HDIs may occur between DB extract and chemicals metabolized or excreted by the liver. Our study revealed that the cardiotoxicity of pirarubicin (THP) was increased by co-administration of DB, and the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in the liver was inhibited by DB extract, which led to the accumulation of THP in heart tissue. In conclusion, there are risks of the co-administration of DB extract and THP. The mechanism of HDIs can be better revealed by targeting the efflux transporters.

Expression of hamster P-glycoprotein and multidrug resistance in DNA-mediated transformants of mouse LTA cells

1987 ◽  
Vol 7 (2) ◽  
pp. 718-724
Author(s):  
K L Deuchars ◽  
R P Du ◽  
M Naik ◽  
D Evernden-Porelle ◽  
N Kartner ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dna Sequences ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Recipient Mouse ◽  
Strongly Correlated ◽  
Wild Type ◽  
Glycoprotein P ◽  
Single Drug ◽  
P Glycoprotein

The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.

scholarly journals Pharmacokinetic Alteration of Paclitaxel by Ferulic Acid Derivative

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 593 ◽  
Author(s):  
Jaeok Lee ◽  
Song Wha Chae ◽  
LianJi Ma ◽  
So Yeon Lim ◽  
Sarah Alnajjar ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Ferulic Acid ◽  
Acid Derivative ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Substrate Drug

P-glycoprotein (P-gp) is known to be involved in multidrug resistance (MDR) and modulation of pharmacokinetic (PK) profiles of substrate drugs. Here, we studied the effects of synthesized ferulic acid (FA) derivatives on P-gp function in vitro and examined PK alteration of paclitaxel (PTX), a well-known P-gp substrate drug by the derivative. Compound 5c, the FA derivative chosen as a significant P-gp inhibitor among eight FA candidates by in vitro results, increased PTX AUCinf as much as twofold versus the control by reducing PTX elimination in rats. These results suggest that FA derivative can increase PTX bioavailability by inhibiting P-gp existing in eliminating organs.

DJ-1 is involved in the multidrug resistance of SGC7901 gastric cancer cells through PTEN/PI3K/Akt/Nrf2 pathway

2020 ◽  
Vol 52 (11) ◽  
pp. 1202-1214
Author(s):  
Lejia Qiu ◽  
Zhaoxia Ma ◽  
Xiaoran Li ◽  
Yizhang Deng ◽  
Guangling Duan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Glycoprotein P ◽  
Nrf2 Pathway ◽  
P Glycoprotein ◽  
New Findings ◽  
Nrf2 Signaling Pathway ◽  
Common Malignancy

Abstract Gastric cancer is a common malignancy worldwide. The occurrence of multidrug resistance (MDR) is the major obstacle for effective gastric cancer chemotherapy. In this study, the in-depth molecular mechanism of the DJ-1-induced MDR in SGC7901 gastric cancer cells was investigated. The results showed that DJ-1 expression level was higher in MDR variant SGC7901/VCR cells than that in its parental SGC7901 cells. Moreover, DJ-1 overexpression conferred the MDR phenotype to SGC7901 cells, while DJ-1 knockdown in SGC7901/VCR cells induced re-sensitization to adriamycin, vincristine, cisplatin, and 5-fluorouracil. These results suggested that DJ-1 mediated the development of MDR in SGC7901 gastric cancer cells. Importantly, further data revealed that the activation of PI3k/Akt and Nrf2 signaling pathway were required for the DJ-1-induced MDR phenotype in SGC7901 gastric cancer cells. Meanwhile, we found that PI3k/Akt pathway was activated probably through DJ-1 directly binding to and negatively regulating PTEN, consequently resulting in Nrf2 phosphorylation and activation, and thereby inducing Nrf2-dependent P-glycoprotein (P-gp) and Bcl-2 expressions in the DJ-1-mediated MDR of SGC7901 gastric cancer cells. Overall, these results revealed that activating PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating P-gp and Bcl-2 expression could be a critical mechanism by which DJ-1 mediates the development of MDR in SGC7901 gastric cancer cells. The new findings may be helpful for understanding the mechanisms of MDR in gastric cancer cells, prompting its further investigation as a molecular target to overcome MDR.

scholarly journals Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis [see comments]

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 473-476 ◽  
Author(s):  
L Campos ◽  
D Guyotat ◽  
E Archimbaud ◽  
P Calmard-Oriol ◽  
T Tsuruo ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Remission Rate ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Clinical Value ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
The Difference ◽  
Acute Nonlymphoblastic Leukemia ◽  
French American British

Abstract To evaluate the clinical value of the expression of multidrug resistance P-glycoprotein (P-170) on the surface of acute nonlymphoblastic leukemia (ANLL) cells, we analyzed specimens from 150 newly diagnosed patients for staining with MRK16, a monoclonal antibody (MoAb) that binds to an external epitope of P-170. Other surface markers (CD13, CD14, CD15, and CD34) were studied by the same technique. A marker was considered positive when 20% or more cells were stained. Of 150 samples, 71 were P-170-positive. These cases did not differ from P-170-negative cases with regard to age, sex, initial white blood cell (WBC) counts, or French-American-British (FAB) type (except for M3 ANLL, which were more frequently negative). However, leukemias arising from previous myelodysplastic syndrome (MDS) and therapy- induced leukemias were more frequently P-170-positive. CD34 and P-170 expression were significantly associated. All patients were treated by intensive chemotherapy. Complete remission (CR) rates were significantly lower in P-170-positive (23/71, 32%) than in P-170- negative cases (64/79, 81%) (P less than 10(-5)). CD34 positivity was also associated with a low remission rate (P less than 10(-5)). Survival was shorter for P-170- and CD34-positive patients (P less than 10(-5)). The prognostic value of both markers was confirmed in multivariate analysis. CR duration was also shorter for P-170-positive cases, but the difference is less significant (P = .05). It is concluded that P-170 analysis may be an important tool for predicting the outcome of intensive chemotherapy in ANLL patients.

Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis [see comments]

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 473-476 ◽  
Author(s):  
L Campos ◽  
D Guyotat ◽  
E Archimbaud ◽  
P Calmard-Oriol ◽  
T Tsuruo ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Remission Rate ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Clinical Value ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
The Difference ◽  
Acute Nonlymphoblastic Leukemia ◽  
French American British

To evaluate the clinical value of the expression of multidrug resistance P-glycoprotein (P-170) on the surface of acute nonlymphoblastic leukemia (ANLL) cells, we analyzed specimens from 150 newly diagnosed patients for staining with MRK16, a monoclonal antibody (MoAb) that binds to an external epitope of P-170. Other surface markers (CD13, CD14, CD15, and CD34) were studied by the same technique. A marker was considered positive when 20% or more cells were stained. Of 150 samples, 71 were P-170-positive. These cases did not differ from P-170-negative cases with regard to age, sex, initial white blood cell (WBC) counts, or French-American-British (FAB) type (except for M3 ANLL, which were more frequently negative). However, leukemias arising from previous myelodysplastic syndrome (MDS) and therapy- induced leukemias were more frequently P-170-positive. CD34 and P-170 expression were significantly associated. All patients were treated by intensive chemotherapy. Complete remission (CR) rates were significantly lower in P-170-positive (23/71, 32%) than in P-170- negative cases (64/79, 81%) (P less than 10(-5)). CD34 positivity was also associated with a low remission rate (P less than 10(-5)). Survival was shorter for P-170- and CD34-positive patients (P less than 10(-5)). The prognostic value of both markers was confirmed in multivariate analysis. CR duration was also shorter for P-170-positive cases, but the difference is less significant (P = .05). It is concluded that P-170 analysis may be an important tool for predicting the outcome of intensive chemotherapy in ANLL patients.

Detection of P-glycoprotein in ovarian cancer: a molecular marker associated with multidrug resistance.

1985 ◽  
Vol 3 (3) ◽  
pp. 311-315 ◽  
Author(s):  
D R Bell ◽  
J H Gerlach ◽  
N Kartner ◽  
R N Buick ◽  
V Ling
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Resistance Mutation ◽  
Advanced Ovarian Cancer ◽  
Surface Glycoprotein ◽  
Glycoprotein P ◽  
Cell Surface Glycoprotein ◽  
P Glycoprotein ◽  
Mutant Lines

A multidrug resistance phenotype is frequently observed in animal and human cell lines selected for in vitro resistance to a single chemotherapeutic agent. Overexpression of a highly conserved cell-surface glycoprotein (P-glycoprotein) is consistently associated with this phenotype in these mutant lines. A monoclonal antibody against P-glycoprotein was used to examine tumor samples from five patients with advanced ovarian cancer for evidence of P-glycoprotein overexpression. High levels of P-glycoprotein were detected in samples from two patients suggesting that a multidrug resistance mutation may also occur in ovarian cancer. This finding has broad implications for the understanding of nonresponse to chemotherapy in a variety of human neoplasms, and may provide a rational explanation for failure of chemotherapy in treatment of advanced ovarian cancer.

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