• Journal of Integrative Natural Science
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• v.4 no.1
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• pp.23-30
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• 2011

Multidrug resistance (MDR) is one of the main obstacles in the chemotherapy of cancer. MDR is associated with the over expression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents were limited by unacceptable toxicity, whereas second-generation agents had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on drug metabolism and no clinically significant drug interactions with common chemotherapy agents. Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.

• Journal of Integrative Natural Science
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• v.5 no.2
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• pp.72-78
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• 2012

Multidrug resistance is a major obstacle in cancer chemotherapy. Cancer cells efflux chemotherapeutic drug out of cell by means of transporter and reduce the active concentration of it inside cell. Such transporters are member of the ATP binding cassettes (ABC) protein. It includes P-gp, multiple resistant protein (MRP), and breast cancer resistant protein (BCRP). These proteins are widely distributed in the human cells such as kidney, lung, endothelial cells of blood brain barrier etc. However, there are number of drugs developed for it, but most of them are getting transported by it. So, still there is necessity of a good modulator, which could effectively combat the transport of chemotherapeutic agents. Natural products origin modulators were found to be effective against transporter such as flavonoids, which belongs to third generation modulators. They have advantage over synthetic inhibitor in the sense that they have simple structure and abundant in nature. This review focuses on the P-gp structure its architecture, efflux mechanism, herbal inhibitors and their mechanism of action.

• Journal of Microbiology and Biotechnology
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• v.18 no.5
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• pp.845-851
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• 2008

TolC is an outer membrane porin protein and an essential component of drug efflux and type-I secretion systems in Gram-negative bacteria. TolC comprises a periplasmic $\alpha$-helical barrel domain and a membrane-embedded $\beta$-barrel domain. TdeA, a functional and structural homolog of TolC, is required for toxin and drug export in the pathogenic oral bacterium Actinobacillus actinomycetemcomitans. Here, we report the expression of the periplasmic domain of TdeA as a soluble protein by substitution of the membrane-embedded domain with short linkers, which enabled us to purify the protein in the absence of detergent. We confirmed the structural integrity of the TdeA periplasmic domain by size-exclusion chromatography, circular dichroism spectroscopy, and electron microscopy, which together showed that the periplasmic domain of the TolC protein family fold correctly on its own. We further demonstrated that the periplasmic domain of TdeA interacts with peptidoglycans of the bacterial cell wall, which supports the idea that completely folded TolC family proteins traverse the peptidoglycan layer to interact with inner membrane transporters.

• Bulletin of the Korean Chemical Society
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• v.35 no.8
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• pp.2317-2325
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• 2014

P-glycoprotein (P-gp) is a member of the ATP-Binding Cassette transporter superfamily and mediates transmembrane efflux of many drugs. Since it is involved in multi-drug resistance activity in various cancer cells, the development of P-gp inhibitor is one of the major concerns in anticancer therapy. Human P-gp protein has at least two "functional" drug binding sites that are called "H" site and "R" site, hence it has multi-binding-specificities. Though the amino acid residues that constitute in drug binding pockets have been proposed by previous experimental evidences, the shapes and the binding poses are not revealed clearly yet. In this study, human P-gp structure was built by homology modeling with available crystal structure of mouse P-gp as a template and docking simulations were performed with inhibitors such as verapamil, hoechst33342, and rhodamine123 to construct the interaction between human P-gp and its inhibitors. The docking simulations were performed 500 times for each inhibitor, and then the interaction frequency of the amino acids at the binding poses was analyzed. With the analysis results, we proposed highly contributing residues that constitute binding pockets of the human P-gp for the inhibitors. Using the highly contributing residues, we proposed the locations and the shapes of verapamil binding site and "R" site, and suggested the possible position of "H" site.

• Journal of Pharmaceutical Investigation
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• v.41 no.5
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• pp.295-300
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• 2011

Paclitaxel is a well known anticancer agent and has been a pharmaceutical challenge because of its extremely poor water-solubility and susceptibility to the p-glycoprotein (p-gp)-mediated efflux in multi-drug resistant (MDR) cancer cells. Tributyrin (TB), a triglyceride with relatively short fatty acid chains, was chosen as solubilizing vehicle for paclitaxel based on the solubility study (26.6 mg/mL). Tributyrin (10%) o/w emulsion containing paclitaxel (5%), egg phosphatidylcholine (5%) and pegylated phospholipid (0.5%) was prepared by high pressure homogenization to obtain submicron-sized emulsion. The mean particle size of the resultant TB emulsion was 395.5 nm. Paclitaxel in TB emulsion showed higher anticancer activity against human breast cancer cell line, MCF-7, than free form delivered in DMSO solution. On the other hand, its anticancer activity was significantly reduced in MCF-7/ADR, a MDR variant cancer cell line of MCF-7, and recovered by the presence of verapamil, suggesting of the susceptibility to the p-gp mediated efflux even though paclitaxel was encapsulated into emulsion. The TB emulsion showed great potential as a promising vehicle for water-insoluble anticancer agent, paclitaxel.

• Archives of Pharmacal Research
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• v.19 no.5
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• pp.353-358
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• 1996

E. coli 11 and E. coli 101, clinical isolates of Escherichia coli were resistant to various quinolones, especially MICs to norfloxacin of both strains were higher than 100 mg/ml. In the presence of carbonyl cyanide m-chlorophenylhydrazone, a proton gradient uncoupler, norfloxacin uptake in both strains was increased, suggesting that an efflux system play an important role in the norfloxacin resistance. Outer membrane proteins of the susceptible and resistant strains which could affect the route of norfloxacin entry into cells were different. When quinolone resistance determining region(QRDR) of gyrA was amplified using PCR and cut with Hinf I, QRDR in the susceptible strain yielded two fragments while QRDRs in E. coli 11 and E. coli 101 yielded only one uncut fragment. When DNA sequence of QRDR was analyzed, there were two mutations as Ser-83 and Asp-87 in both resistant strains. these residues were changed to Leu-83 and Asn-87, respectively. These results showed that the norfloxacin resistance of E. coli 11 and E. coli 101 was resulted from multiple changes-an altered DNA gyrase A subunit, a change in route of drug entry, and reduction in quinolone concentration inside cells due to an efflux system.

• BMB Reports
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• v.52 no.5
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• pp.330-335
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• 2019

Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.2
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• pp.107-122
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• 2001

A function of the kidney is elimination of a variety of xenobiotics ingested and wasted endogenous compounds from the body. Organic anion and cation transport systems play important roles to protect the body from harmful substances. The renal proximal tubule is the primary site of carrier-mediated transport from blood into urine. During the last decade, molecular cloning has identified several families of multispecific organic anion and cation transporters, such as organic anion transporter (OAT), organic cation transporter (OCT), and organic anion-transporting polypeptide (oatp). Additional findings also suggested ATP-dependent organic ion transporters such as MDR1/P-glycoprotein and the multidrug resistance-associated protein (MRP) as efflux pump. The substrate specificity of these transporters is multispecific. These transporters also play an important role as drug transporters. Studies on their functional properties and localization provide information in renal handling of drugs. This review summarizes the latest knowledge on molecular properties and pharmacological significance of renal organic ion transporters.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6849-6853
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• 2014

Multidrug resistance (MDR) is a major impediment to successful chemotherapy of gastric cancer. Our aim was to establish an epirubicin-resistant cell subline (AGS/EPI) and to elucidate the mechanisms involved in acquired EPI resistance. The AGS/EPI cell subline developed by exposing parental AGS cells to stepwise increasing concentrations of EPI demonstrated 2.52-fold resistance relative to the AGS cell line, and mRNA expression of the ATP-dependent drug-efflux pump P-glycoprotein (Pgp), more recently known as ABCB1 protein, was similarly upregulated. An AGS/EPI cell subline could thus be effectively established, and MDR mechanism of these cells was shown to be related to the overexpression of mRNA of the ABCB1 gene.

• Korean Journal of Clinical Pharmacy
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• v.20 no.1
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• pp.25-29
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• 2010

The purpose of this study was to investigate the effect of atorvastatin on the pharmacokinetics of nifedipine (6 mg/kg) after oral administration of nifedipine with or without atorvastatin (0.5 and 2.0 mg/kg) in rats, and also was to evaluate to the effect of atorvastatin on the CYP3A4 activity. The 50% inhibiting concentration ($IC_{50}$) values of atorvastatin on CYP3A4 activity is 46.1 ${\mu}M$. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner. Coadministration of atorvastatin increased significantly (p<0.05, 2.0 mg/kg) the plasma concentration-time curve (AUC) and the peak concentration ($C_{max}$) of nifedipine compared to the control group. The relative bioavailability (RB%) of nifedipine was increased from 1.15- to 1.37-fold. Coadministration of atorvastatin did not significantly change the terminal half-life ($T_{1/2}$) and the time to reach the peak concentration ($T_{max}$) of nifedipine. Based on these results, we can make a conclusion that the significant changes of these pharmacokinetic parameters might be due to atorvastatin, which possesses the potency to inhibit the metabolizing enzyme (CYP3A4) in the liver and intestinal mucosa, and also inhibit the P-glycoprotein (P-gp) efflux pump in the intestinal mucosa. It might be suggested that atorvastatin altered disposition of nifedipine by inhibition of both the first-pass metabolism and P-glycoprotein efflux pump in the small intestine of rats. In conclusion, the presence of atorvastatin significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of atorvastatin with nifedipine should require close monitoring for potential drug interation.