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1.
M Ichikawa A Yoshimura T Furukawa T Sumizawa Y Nakazima S Akiyama 《Biochimica et biophysica acta》1991,1073(2):309-315
P-glycoprotein (P-gp) is thought to transport anti-cancer drugs and to be responsible for the multidrug-resistant (MDR) phenotype. Immunohistochemistry reveals that P-gp is also expressed in normal human tissues, such as the adrenal gland, kidney, liver, and the capillary endothelium of the brain and testis. However, little is known about the structural and functional variations of P-gp in these tissues. With immunoblotting and photoaffinity labeling, we found that the molecular mass of P-gp in these tissues varied between 130-140 kDa. To clarify the post-translational modification of P-gp, we studied the biosynthesis of P-gp in a human multidrug-resistant cell line (KB-C2). We found that P-gp was produced in KB-C2 cells as a 125 kDa precursor and was slowly processed (t1/2 = 45-60 min) to the mature form of 140 kDa. In the presence of tunicamycin, a 120 kDa form of P-gp was synthesized and this form was no longer processed. Treating the 125 kDa precursor form with endo-beta-N-acetylglucosaminidase H (Endo H) and the 140 kDa mature form with N-glycanase diminished the molecular size of P-gp to that of the tunicamycin-treated form. N-Glycanase almost completely removed [3H]glucosamine labeling from P-gp. These data indicate that the major modification of P-gp is N-linked glycosylation. P-gps from KB-C2 cells, kidney and adrenal gland had a different lectin-binding capacity. There seems to be a variety of N-linked glycosylations in tissue and tumor P-gps. 相似文献
2.
M Ichikawa A Yoshimura T Furukawa T Sumizawa S Akiyama 《Biochemical and biophysical research communications》1990,166(1):74-80
P-glycoprotein (P-gp) is thought to mediate the transport of anticancer drugs and to be responsible for the multidrug-resistant (MDR) phenotype. P-gp is also expressed in normal human tissues, such as the adrenal gland, kidney, liver, colon and capillary endothelium of the brain. However, the function and transporting substrates of P-gp in normal tissues are still not understood. This paper explains that some compounds in the human plasma can modulate the transporting activity of P-gp. A partially purified fraction from the human plasma enhanced the accumulation of anti-cancer agents in MDR cells. This fraction inhibited the efflux of vinblastine from MDR cells, and also inhibited the photoaffinity labeling of P-gp with azidopine as effectively as vinblastine, quinidine and cepharanthine. The compounds in this purified fraction may be physiological substrates of P-gp and can probably overcome MDR. 相似文献
3.
Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols 总被引:11,自引:0,他引:11
Many beneficial proprieties have been associated with polyphenols from green tea, such as chemopreventive, anticarcinogenic, antiatherogenic and antioxidant actions. In this study, we investigated the effects of green tea polyphenols (GTPs) and their principal catechins on the function of P-glycoprotein (P-gp), which is involved in the multidrug resistance phenotype of cancer cells. GTPs (30 microg/ml) inhibit the photolabeling of P-gp by 75% and increase the accumulation of rhodamine-123 (R-123) 3-fold in the multidrug-resistant cell line CH(R)C5, indicating that GTPs interact with P-gp and inhibit its transport activity. Moreover, the modulation of P-gp transport by GTPs was a reversible process. Among the catechins present in GTPs, EGCG, ECG and CG are responsible for inhibiting P-gp. In addition, EGCG potentiates the cytotoxicity of vinblastine (VBL) in CH(R)C5 cells. The inhibitory effect of EGCG on P-gp was also observed in human Caco-2 cells, which form an intestinal epithelial-like monolayer. Our results indicate that, in addition to their anti-cancer properties, GTPs and more particularly EGCG inhibit the binding and efflux of drugs by P-gp. Thus, GTPs or EGCG might be potential agents for modulating the bioavailability of P-gp substrates at the intestine and the multidrug resistance phenotype associated with expression of this transporter in cancer cells. 相似文献
4.
The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles 总被引:16,自引:0,他引:16
Y Kamimoto Z Gatmaitan J Hsu I M Arias 《The Journal of biological chemistry》1989,264(20):11693-11698
Gp170 (also known as P-glycoprotein) is a transmembrane glycoprotein which is overexpressed in multidrug-resistant tumor cells and is also found in the apical plasma membrane domain of several normal human and animal tissues. Gp170 has been postulated to function as an energy-dependent efflux pump for cytotoxic drugs. In rat liver, Gp170 is restricted to the bile canalicular domain of the plasma membrane. Canalicular membrane vesicles (CMV), but not sinusoidal membrane vesicles, contained a approximately 160-kDa protein which reacts with anti-Gp170 monoclonal antibody and manifest ATP-dependent [3H]daunomycin transport which is temperature dependent, osmotically sensitive, and saturable. Among several nucleotides, ATP was a potent stimulator of transport whereas non- or slowly hydrolyzable analogues (adenosin-5-O-(3-thiotriphosphate, adenyl-5-yl-imidodiphosphate) were ineffective. ATP-dependent daunomycin transport was inhibited by cytotoxic drugs (vinblastine, vincristine, and adriamycin) and other drugs, such as verapamil and quinidine, which restore anti-cancer drug sensitivity in resistant cells. Inside-out CMV were separated from right side-out CMV by antibody-induced affinity density perturbation. Only inside-out CMV manifested ATP-dependent daunomycin transport. These results suggest that Gp170 is an ATP-dependent efflux pump which is responsible for the undirectional, energy-dependent transport of daunomycin and other drugs by rat liver into the bile. 相似文献
5.
Wang EJ Barecki-Roach M Johnson WW 《Biochemical and biophysical research communications》2002,297(2):412-418
The ABC transporter P-glycoprotein (P-gp) exerts a critical role in the systemic disposition of and exposure to lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics. The ability of P-gp to transfer a wide variety of structurally unrelated compounds from the cell interior across the membrane bilayer remains intriguing. Since dietary chemicals in green tea (and several other foods) appear to exert anticarcinogenic effects by an unknown mechanism, the constituents are frequently studied for interactions with various biomacromolecules as well as cytotoxins or isolated cells. We characterized several green tea catechins for their interaction with P-gp and their specific effects on P-gp export activity of several marker substrates. Some of these compounds inhibit the active efflux of the fluorescent markers LDS-751 (LDS) and rhodamine 123 (Rho) with low potency. Remarkably, others of these catechins facilitate the P-gp-mediated transport of LDS without affecting daunorubicin (DNR) transport or Rho. Moreover, (-)epicatechin, though an inhibitor of Rho transport, can significantly enhance the active net transport of another P-gp marker substrate, LDS. This result indicates that (-)epicatechin may bind to and activate an allosteric site that enhances P-gp overall function or efficiency. Such a mechanism of heterotropic allosteric enhancement of P-gp could serve as chemoprotective to many cells and contribute to the purported anticarcinogenic effect of green tea consumption. 相似文献
6.
Nabekura T Yamaki T Ueno K Kitagawa S 《Biochemical and biophysical research communications》2008,369(2):363-368
The effects of dietary plant sterols on human drug efflux transporters P-glycoprotein (P-gp, ABCB1) and multidrug resistance protein 1 (MRP1, ABCC1) were investigated using P-gp-overexpressing human carcinoma KB-C2 cells and human MRP1 gene-transfected KB/MRP cells. The effects of natural phytosterols found in foods, herbs, and dietary supplements such as β-sitosterol, campesterol, stigmasterol, fucosterol, and z-guggulsterone were investigated. The accumulation of daunorubicin or rhodamine 123, fluorescent substrates of P-gp, increased in the presence of guggulsterone in KB-C2 cells. The efflux of rhodamine 123 from KB-C2 cells was inhibited by guggulsterone. Guggulsterone also increased the accumulation of calcein, a fluorescent substrate of MRP1, in KB/MRP cells. The ATPase activities of P-gp and MRP1 were stimulated by guggulsterone. These results suggest that guggulsterone, a natural dietary hypolipidemic agent have dual inhibitory effects on P-gp and MRP1 and the potencies to cause food-drug interactions. 相似文献
7.
Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. 总被引:26,自引:0,他引:26
K Ueda N Okamura M Hirai Y Tanigawara T Saeki N Kioka T Komano R Hori 《The Journal of biological chemistry》1992,267(34):24248-24252
We expressed human MDR1 cDNA isolated from the human adrenal gland in porcine LLC-PK1 cells. A highly polarized epithelium formed by LLC-GA5-COL300 cells that expressed human P-glycoprotein specifically on the apical surface showed a multidrug-resistant phenotype and had 8.3-, 3.4-, and 6.5-fold higher net basal to apical transport of 3H-labeled cortisol, aldosterone, and dexamethasone, respectively, compared with host cells. But progesterone was not transported, although it inhibited azidopine photoaffinity labeling of human P-glycoprotein and increased the sensitivity of multidrug-resistant cells to vinblastine. An excess of progesterone inhibited the transepithelial transport of cortisol by P-glycoprotein. These results suggest that cortisol and aldosterone are physiological substrates for P-glycoprotein in the human adrenal cortex and that substances that efficiently bind to P-glycoprotein are not necessarily transported by P-glycoprotein. 相似文献
8.
The translocation mechanism of P-glycoprotein 总被引:3,自引:0,他引:3
Multidrug transporters are involved in mediating the failure of chemotherapy in treating several serious diseases. The archetypal multidrug transporter P-glycoprotein (P-gp) confers resistance to a large number of chemically and functionally unrelated anti-cancer drugs by mediating efflux from cancer cells. The ability to efflux such a large number of drugs remains a biological enigma and the lack of mechanistic understanding of the translocation pathway used by P-gp prevents rational design of compounds to inhibit its function. The translocation pathway is critically dependent on ATP hydrolysis and drug interaction with P-gp is possible at one of a multitude of allosterically linked binding sites. However, aspects such as coupling stoichiometry, molecular properties of binding sites and the nature of conformational changes remain unresolved or the centre of considerable controversy. The present review attempts to utilise the available data to generate a detailed sequence of events in the translocation pathway for this dexterous protein. 相似文献
9.
P-glycoprotein (P-gp), the MDR1 multidrug transporter, is known to be expressed in several human organs and tissues, including the apical membrane of the renal proximal tubular cells. It has been reported that human immunodeficiency virus 1 (HIV-1) can trigger the expression of P-gp in cultured cells (i.e., H9, a T-lymphocyte cell line, and U937, a monocyte cell line), which may render the cells resistant to antiretrovirals. Since multiple membrane transport systems (i.e., organic cation, organic anion, and nucleoside systems) can be involved in the renal tubular transport of dideoxynucleoside analog drugs (DADs) (i.e., zidovudine and zalcitabine), we have questioned if P-gp is involved in the renal transport of DADs. Chinese hamster ovary colchicine-resistant cells (CH(R)C5), a cell line that is well known to highly express P-gp, and continuous renal epithelial cell lines (LLC-PK1 and OK), which have also been shown to express P-gp, were used. The accumulation of [3H]vinblastine (20 nM), an established P-gp substrate, by the monolayer cells was significantly enhanced in the presence of two P-gp inhibitors (i.e., verapamil and cyclosporin A) and nucleoside transport inhibitors (i.e., dipyridamole and dilazep). In contrast, DADs (i.e., zidovudine, lamivudine, didanosine, and zalcitabine) did not significantly affect vinblastine accumulation by these cell lines. These data suggest that P-gp does not play a significant role in the renal tubular transport of DADs. Dipyridamole and dilazep, two nucleoside membrane transport inhibitors, appear to be P-gp inhibitors. 相似文献
10.
:ABCC4、ABCC5是ABCC(ATP-binding cassette transporter family class C, ABCC)蛋白转运体家族的成员,介导众多内源性代谢产物和外源性药物从细胞内向外转运。ABCC4和ABCC5在体内分布广泛,参与机体对药物和内、外源物质的吸收、分布和排泄等。ABCC4、ABCC5的一些突变会引起转运体表达、功能的改变和机体对药物反应的改变。近年研究发现ABCC4、ABCC5与某些肿瘤的多药耐药相关,转运体的过表达可以引起肿瘤细胞对多种肿瘤化疗药物的耐药性,导致临床化疗效果不佳。本文就转运体ABCC4和ABCC5介导的肿瘤多药耐药研究进展进行综述。 相似文献
11.
ABCC4、ABCC5 是ABCC(ATP-binding cassette transporter family class C, ABCC)蛋白转运体家族的成员,介导众多内源性
代谢产物和外源性药物从细胞内向外转运。ABCC4和ABCC5 在体内分布广泛,参与机体对药物和内、外源物质的吸收、分布和
排泄等。ABCC4、ABCC5 的一些突变会引起转运体表达、功能的改变和机体对药物反应的改变。近年研究发现ABCC4、ABCC5
与某些肿瘤的多药耐药相关,转运体的过表达可以引起肿瘤细胞对多种肿瘤化疗药物的耐药性,导致临床化疗效果不佳。本文就
转运体ABCC4和ABCC5 介导的肿瘤多药耐药研究进展进行综述。 相似文献
12.
Ushijima H Hiasa M Namba T Hwang HJ Hoshino T Mima S Tsuchiya T Moriyama Y Mizushima T 《Biochemical and biophysical research communications》2008,374(2):325-330
In contrast to transport across basolateral membranes, the mechanism governing transport of organic anions across the luminal membranes of proximal tubules has remained unclear. We recently found Tetracycline transporter-like protein (TETRAN), a human ortholog of yeast Tpo1p that can transport anionic Non-steroidal anti-inflammatory drugs (NSAIDs). In this study, we examine the expression and function of TETRAN. TETRAN mRNA is expressed in various human tissues, including kidney. When overexpressed in cultured cells, TETRAN was predominantly localized on cytoplasmic membranes. Immunohistochemical analysis of human and mouse kidney tissue showed that TETRAN was expressed at the luminal membranes of proximal tubules. Overexpression of TETRAN in cultured cells facilitated the uptake of organic anions such as indomethacin (a NSAID) and fluorescein. The results suggest that TETRAN is a novel human organic anion transporter, and that it serves as a transporter for some NSAIDs and various other organic anions at the final excretion step. 相似文献
13.
Biosynthesis, processing and half-life of P-glycoprotein in a human multidrug-resistant KB cell 总被引:1,自引:0,他引:1
A Yoshimura Y Kuwazuru T Sumizawa S Ikeda M Ichikawa T Usagawa S Akiyama 《Biochimica et biophysica acta》1989,992(3):307-314
The biosynthesis, processing, and half-life of the drug efflux pump, P-glycoprotein, were studied in human multidrug-resistant KB (KB-C2) cells selected for resistance to colchicine. An antibody directed against a synthetic oligopeptide corresponding to the amino-acid sequence (Glu-393-Lys-408) of P-glycoprotein from human mdr1 cDNA was prepared in rabbits. With immunoblotting and immunoprecipitation, we detected a 140-170 kDa protein in KB-C2 cells but not in parental sensitive KB cells. KB-C2 cells made a 125 kDa precursor that was slowly processed (t1/2 = 45 min) to the mature form of 140-150 kDa. The processing rate of P-glycoprotein was slower than that of low-density lipoprotein receptor. We detected another 160-180 kDa smear band, which might be a completely denatured form of P-glycoprotein. With immunoblotting, a minor band of high molecular mass (greater than 500 kDa) was also detected and this form increased after the cells were treated with chemical cross-linker, 1,5-difluoro-2,4-dinitrobenzene. The half-life of P-glycoprotein was long; no significant loss of P-glycoprotein was observed within 24 h after synthesis. Cells treated with tunicamycin produced a 120 kDa form of P-glycoprotein which was no longer processed but showed stability similar to that of the mature 140-150 kDa form. Agents that reverse multidrug resistance, phorbol ester and transport substrate did not affect the stability of P-glycoprotein. 相似文献
14.
Immunocytochemical localization of P170 at the plasma membrane of multidrug-resistant human cells 总被引:11,自引:0,他引:11
M C Willingham N D Richert M M Cornwell T Tsuruo H Hamada M M Gottesman I H Pastan 《The journal of histochemistry and cytochemistry》1987,35(12):1451-1456
P170 (P-glycoprotein) is a membrane protein found in high levels in multidrug-resistant cultured cell lines. We have localized this protein using monoclonal antibody MRK16 by immunofluorescence and electron microscopy in the multidrug-resistant human carcinoma cell line KB-C4. The P170 determinant recognized by antibody MRK16 was found on drug-resistant KB-C4 cells, but not on parental drug-sensitive KB-3-1 cells. The determinant was present on the external surface of the plasma membrane and on the luminal side of Golgi stack membranes. P170 was excluded from coated pits at the plasma membrane and absent from endocytic vesicles and lysosomes. This determinant was detected only in small amounts in the endoplasmic reticulum. The high protein concentration of P170 in the plasma membrane is consistent with a role of this protein as a drug efflux pump at the cell surface. 相似文献
15.
Ritter M Buechler C Boettcher A Barlage S Schmitz-Madry A Orsó E Bared SM Schmiedeknecht G Baehr CH Fricker G Schmitz G 《Genomics》2002,79(5):693-702
Apolipoprotein A-I (apoA-I) is the major apolipoprotein of high-density lipoproteins (HDL) and has an important role in the regulation of the stability, lipid transport, and metabolism of HDL particles. To identify novel proteins that are involved in HDL metabolism, we used mature apoA-I (amino acids 25-267) as a bait for the screening of a human liver two-hybrid cDNA library. Among the identified genes, several encoded known proteins, including serum amyloid A(2a) (SAA(2a)), apoC-I, and phosphodiesterase HCAM1 (PDE1A), found to interact with apoA-I. In addition, we have cloned a novel 29 kDa apoA-I interacting protein, which we named AI-BP (apoA-I binding protein). The AI-BP encoding gene, APOA1BP, which is located on chromosome 1q21, is composed of six exons and five introns and spans 2.5 kb. Northern blot analysis demonstrated ubiquitous expression of the APOA1BP mRNA with the highest expression in kidney, heart, liver, thyroid gland, adrenal gland, and testis. AI-BP protein is not detectable in serum of healthy probands, but serum samples of patients with septic syndromes may contain elevated levels of AI-BP. Significant amounts of AI-BP protein are found in cerebrospinal fluid and urine of healthy probands. The stimulation of cells derived from the kidney proximal tubules with apoA-I or HDL induces a concentration-dependent secretion of AI-BP indicating an important role for AI-BP, in the renal tubular degradation or resorption of apoA-I. 相似文献
16.
Smith AJ van Helvoort A van Meer G Szabo K Welker E Szakacs G Varadi A Sarkadi B Borst P 《The Journal of biological chemistry》2000,275(31):23530-23539
The human MDR3 gene is a member of the multidrug resistance (MDR) gene family. The MDR3 P-glycoprotein is a transmembrane protein that translocates phosphatidylcholine. The MDR1 P-glycoprotein related transports cytotoxic drugs. Its overexpression can make cells resistant to a variety of drugs. Attempts to show that MDR3 P-glycoprotein can cause MDR have been unsuccessful thus far. Here, we report an increased directional transport of several MDR1 P-glycoprotein substrates, such as digoxin, paclitaxel, and vinblastine, through polarized monolayers of MDR3-transfected cells. Transport of other good MDR1 P-glycoprotein substrates, including cyclosporin A and dexamethasone, was not detectably increased. MDR3 P-glycoprotein-dependent transport of a short-chain phosphatidylcholine analog and drugs was inhibited by several MDR reversal agents and other drugs, indicating an interaction between these compounds and MDR3 P-gp. Insect cell membranes from Sf9 cells overexpressing MDR3 showed specific MgATP binding and a vanadate-dependent, N-ethylmaleimide-sensitive nucleotide trapping activity, visualized by covalent binding with [alpha-(32)P]8-azido-ATP. Nucleotide trapping was (nearly) abolished by paclitaxel, vinblastine, and the MDR reversal agents verapamil, cyclosporin A, and PSC 833. We conclude that MDR3 P-glycoprotein can bind and transport a subset of MDR1 P-glycoprotein substrates. The rate of MDR3 P-glycoprotein-mediated transport is low for most drugs, explaining why this protein is not detectably involved in multidrug resistance. It remains possible, however, that drug binding to MDR3 P-glycoprotein could adversely affect phospholipid or toxin secretion under conditions of stress (e.g. in pregnant heterozygotes with one MDR3 null allele). 相似文献
17.
Renate Lüllmann-Rauch Brigitte Stoermer 《Virchows Archiv. B, Cell pathology including molecular pathology》1982,39(1):59-73
Pregnant rats and guinea pigs were treated throughout the second half of gestation with amphiphilic drugs (chlorphentermine, chlorcyclizine, chloroquine) known to induce generalized lipidosis. The offspring were sacrificed immediately after birth, and several tissues (lung, liver, kidney, spleen, pituitary gland, adrenal gland, spinal cord, hypothalamus) were examined by electron microscopy. Generalized lipidosis was found in the offspring of both species, albeit of lesser degree than in the mothers. The results show that fetal and adult tissues respond to lipidosis-inducing drugs in a qualitatively similar way; the quantitative differences found may be related to pharmacokinetic and cellular factors. 相似文献
18.
Paul A. Dawson Melissa L. HubbertAnuradha Rao 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2010,1801(9):994-1004
The organic solute transporter (OST)(alpha)-OST(beta) is an unusual heteromeric carrier expressed in a variety of tissues including the small intestine, colon, liver, biliary tract, kidney, and adrenal gland. In polarized epithelial cells, OSTα-OSTβ protein is localized on the basolateral membrane and functions in the export or uptake of bile acids and steroids. This article reviews recent results including studies of knockout mouse models that provide new insights to the role of OSTα-OSTβ in the compartmentalization and metabolism of these important lipids. 相似文献
19.
Reversal of multidrug resistance by calcium channel blocker SR33557 without photoaffinity labeling of P-glycoprotein 总被引:5,自引:0,他引:5
J P Jaffrézou J M Herbert T Levade M N Gau P Chatelain G Laurent 《The Journal of biological chemistry》1991,266(29):19858-19864
The altered pharmacology of drugs in multidrug-resistant cells (decreased accumulation and retention) appears to be mediated by a high molecular weight integral membrane protein, called P-glycogprotein (P-gp). Agents known to reverse this pleiotropic drug resistance (chemosensitizers) have been shown to interact with P-gp; and as such, the inhibition of photoaffinity labeling by P-gp probes (such as [3H]azidopine) has been proposed as a basis for mass screening of chemosensitizers. In this study, we provide direct evidence that a novel calcium channel blocker (SR33557), which was 4.5 times more potent in sensitizing P388/ADR cells to doxorubicin as compared to verapamil (while inducing a similar increase in uptake and decrease in efflux of [14C]doxorubicin, did not compete for the [3H]azidopine-binding site on P-gp, whereas verapamil did. Moreover, SR33557, which is inherently photoactivable, did not photolabel P-gp, but a 65-kDa protein did appear to be an acceptor; and this binding was displaced by diltiazem and nifedipine, but not by verapamil. Finally, the implication for the participation of a sphingomyelin/sphingosine cycle (as a potential lipid second messenger system) in the chemosensitization of P388/ADR cells was investigated. 30 microM SR33557 induced a 72% inhibition in acid lysosomal sphingomyelinase activity, a 5-fold increase in sphingosine levels, and a 75% inhibition in intracellular protein kinase C activity. Although no direct link is established between these observations and P-gp activity, further studies on a possible sphingosine-mediated regulation of P-gp may yield information on the involvement of this second messenger system in the action of SR33557. 相似文献
20.
Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, has been applied in phase II clinical trial as second-line treatment for advanced gastric cancer. In this study, we determined the effect of Sunitinib on the multidrug resistance in gastric cancer cells selected by vincristine. Our results showed that Sunitinib significantly enhanced the cytotoxicity of adriamycin, vincristine, etoposide, 5-Fluorouracil, and cisplatin in multidrug-resistant gastric cancer cells (SGC7901/VCR). Sunitinib significantly increased the intracellular accumulation and retention of rhodamine 123 in the SGC7901/VCR cells. However, Sunitinib, at a concentration that reverses MDR, had no significant effect on P-gp protein or mRNA expression levels. In addition, the present study revealed that Sunitinib inhibited Stat3 and down-regulated Bcl-2 in SGC7901/VCR cells, which might also contribute to the reversal of MDR. In conclusion, Sunitinib reverses multidrug resistance in gastric cancer cells by inhibiting P-gp transporter function and modulating Stat3 and Bcl-2. Further study with Sunitinib may be helpful for developing combination therapeutic strategy or circumventing gastric cancer MDR to other conventional anti-cancer drugs. 相似文献