P-糖蛋白引起的肿瘤多药耐药及其逆转

肿瘤化学治疗最大障碍之一是肿瘤细胞对抗癌药物产生耐受性，1970年国外首次报道了交叉耐药现象。

非小细胞肺癌中COX-2、P-gp的表达及其与人乳头状瘤病毒感染的关系

目的研究非小细胞肺癌(NSCLC)中COX-2、P-gp的表达及两者的相关性,以探讨COX-2在NSCLC多药耐药中的作用;分析NSCLC中COX-2、P-gp表达与人乳头状瘤病毒(HPV)感染的相关性。方法应用免疫组化法检测54例NSCLC及16例肺良性病变组织中COX-2、P-gp蛋白表达,应用PCR法检测两组中HPV16/18 DNA的表达。结果①NSCLC中COX-2和P-gp表达阳性率分别为59.3%(32/54)和46.3%(25/54),远癌正常组织未见阳性表达;②COX-2阳性组中P-gp的表达阳性率为65.6%(21/32),明显高于COX-2阴性组的18.2%(4/22),两者有显著相关性(r=0.468,P<0.05);③肺腺癌中COX-2表达阳性率73.1%(19/26),明显高于肺鳞癌46.4%(13/28)(P<0.05),NSCLC中COX-2表达与患者性别、年龄、肿瘤分化程度、淋巴结转移、TNM分期和吸烟史等无关(均P>0.05);④NSCLC中HPV16/18 DNA总检出率为40.7%(22/54),肺良性病变组为6.3%(1/16),两者差异有显著性意义(P<0.05);32例COX-2阳性的病例中HPV DNA同时阳性有13例,22例COX-2阴性病例中有13例HPV DNA阴性,两者无相关性(P>0.05);HPV DNA阳性组与阴性组间P-gp的阳性表达率分别为40.9%(9/22)及50.0%(16/32),两组间差异无显著性意义(P>0.05)。结论COX-2可能通过上调P-gp的表达而参与对NSCLC多药耐药的调节;NSCLC中COX-2、P-gp表达与HPV感染无协同作用。

大肠癌组织中P-gp、GSTπ、Topo-Ⅱ的表达及临床意义

目的 探讨大肠癌组织中耐药基因旦白P -gp、GST -π和Topo- Ⅱ的表达与病理组织学类型、Dukes分期、淋巴结转移的相关性及其在化疗中的临床指导意义。方法 应用免疫组织化学方法检测53例手术切除的结直肠癌组织中P -gp、GST- π和Topo Ⅱ的表达。结果 结直肠癌组织中P- gp、GST- π和Topo -Ⅱ的阳性率分别为79.25%、54.72%和56.60%。GST -π的表达与结直肠癌的组织学类型相关,而P gp的表达与淋巴结转移相关。Topo- Ⅱ的表达与本组临床病理参数均无相关性。结论 根据P- gp、GST -π和Topo Ⅱ的不同表达,结合各自不同的耐药机制,对肿瘤的化疗药物和方案选择具有重要的临床意义。

Using ^(99m)Tc-MIBI to Evaluate the Effects of Chemosensitizer on P-glycoprotein in Multidrug-resistant Carcinoma Cells

To establish a method to evaluate the effects of chemosensitizer onP-glycoprotein using ^(99m)Tc-MIBI, and observe the changes of ^(99m)Tc-MIBI uptake kinetics andP-glycoprotein levels after using verapamil in MDR human breast cells MCF-7/Adr. Methods: MDR breastcarcinoma cells, MCF-7/Adr, were incubated and different protocols were performed. Protocol Ⅰ: achemosensitizer, verapamil (10 μmol/L), was added into cell culture medium, while in control group,the same volume of DMEM was given. Cells were harvested after 2 h incubation with ^(99m)Tc-MIBI.Protocol Ⅱ: Verapamil (10 μmol/L) was added into cell culture medium and incubated for 20 min, 40min, 60 min, 80 min, 8 h, 24 h, 48 h and 72 h respectively. Cells were harvested after 2 hincubation with ^(99m)Tc-MIBI. The radioactivity of the cells was measured and P-glycoproteinexpression levels were determined with immunohistochemical stain. Results: Protocol Ⅰ: After 2hincubation with verapamil the cellular uptake of ^(99m)Tc-MIBI was remarkably higher than controlgroup (t=2.33, P 【 0.05), but there was no difference in P-glycoprotein expression levels betweentwo groups (P 】 0.05). Protocol Ⅱ: In verapamil group, ^(99m)Tc-MIBI uptake was increased withincubation time prolonging (F=58.2, P 【 0.05). When verapamil incubation time surpassed 8 h the^(99m)Tc-MIBI uptake negatively correlated to the P-glycoprotein expression levels (r=-0.73, P 【0.01). However, when incubation time was less than 80 min, there was no correlation between^(99m)Tc-MIBI accumulation and P-glycoprotein levels (r=0.16, P 】 0.05). Conclusion: ^(99m)Tc-MIBImay be used to evaluate the qualitative as well as quantitative change of P-glycoprotein expressionlevels induced by the chemosensitizer, verapamil.

Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice

AIM:To investigate the adjunct anticancer effect of Astragalus polysaccharides in H22 tumor-bearing mice.METHODS:To establish a solid tumor model,5.0 × 10 6 /mL H22 hepatoma cells were inoculated subcutaneously into the right armpit region of Kunming mice(6-12 wk old,18-22 g).When the tumors reached a size of 100 mm 3,the animals were treated as indicated,and the mice were randomly assigned to seven groups(n = 10 each).After ten days of treatment,blood samples were collected from mouse eyes,and serum was harvested by centrifugation.Mice were sacrificed,and the whole body,tumor,spleen and thymus were weighed immediately.The rate of tumor inhibition and organ indexes were calculated.The expression levels of serum cytokines,P-glycoprotein(P-GP) and multidrug resistance(MDR) 1 mRNA in tumor tissues were detected using enzyme-linked immunosorbent assay,Western blotting,and quantitative myeloid-derived suppressor cells reverse transcription-polymerase chain reaction,respectively.RESULTS:The tumor inhibition rates in the treatment groups of Adriamycin(ADM) + Astragalus polysaccharides(APS)(50 mg/kg),ADM + APS(100 mg/kg),and ADM + APS(200 mg/kg) were significantly higher than in the ADM group(72.88% vs 60.36%,P = 0.013;73.40% vs 60.36%,P = 0.010;77.57% vs 60.36%,P = 0.001).The spleen indexes of the above groups were also significantly higher than in the ADM group(0.65 ± 0.22 vs 0.39 ± 0.17,P = 0.023;0.62 ± 0.34 vs 0.39 ± 0.17,P = 0.022;0.67 ± 0.20 vs 0.39 ± 0.17,P = 0.012),and the thymus indexes of the ADM + APS(100 mg/kg) and ADM + APS(200 mg/kg) groups were significantly higher than in the ADM group(0.20 ± 0.06 vs 0.13 ± 0.04,P = 0.029;0.47 ± 0.12 vs 0.13 ± 0.04,P = 0.000).APS was found to exert a synergistic antitumor effect with ADM and to alleviate the decrease in the sizes of the spleen and thymus induced by AMD.The expression of interleukin-1α(IL-1α),IL-2,IL-6,and tumor necrosis factor-α(TNF-α) was significantly higher in the ADM + APS(50 mg/kg),ADM + APS(100 mg/kg) and ADM + APS(200 mg/kg) groups than in the ADM group;and IL-10 was significantly lower in the above groups than in the ADM group.APS could increase IL-1α,IL-2,IL-6,and TNF-α expression and decrease IL-10 levels.Compared with the ADM group,APS treatment at a dose of 50-200 mg/kg could downregulate MDR1 mRNA expression in a dose-dependent manner(0.48 ± 0.13 vs 4.26 ± 1.51,P = 0.000;0.36 ± 0.03 vs 4.26 ± 1.51,P = 0.000;0.21 ± 0.04 vs 4.26 ± 1.51,P = 0.000).The expression level of P-GP was significantly lower in the ADM + APS(200 mg/kg) group than in the ADM group(137.35 ± 9.20 mg/kg vs 282.19 ± 20.54 mg/kg,P = 0.023).CONCLUSION:APS exerts a synergistic anti-tumor effect with ADM in H22 tumor-bearing mice.This may be related to its ability to enhance the expression of IL1α,IL-2,IL-6,and TNF-α,decrease IL-10,and downregulate MDR1 mRNA and P-GP expression levels.

Relationship between therapeutic efficacy of arterial infusion chemotherapy and expression of P-glycoprotein and p53 protein in advanced hepatocellular carcinoma

AIM： To investigate the relationship between the chemotherapeutic drug efficacy and the expression of P-glycoprotein （PGP） and p53 protein in advanced hepatocellular carcinoma （HCC）. METHODS： The study was conducted on 41 patients with advanced HCC who were treated by repeated arterial infusion chemotherapy. Biopsy specimens from the tumor were collected before the start of treatment in all the patients, and the specimens were stored frozen until immunohistochemical staining, which was performed after the start of treatment, to detect PGP and p53 protein expressions. Twenty of the fortyone patients were treated with an anthracycline drug （epirubicin hydrochloride; anthracycline group）, and the remaining 21 were treated with a non-anthracycline drug （mitoxantrone hydrochloride in 11 patients and carboplatin in 10 patients; non-anthracycline group）. The relationship between the chemotherapeutic efficacy and the results of immunostaining were compared between the two groups. RESULTS： Before the start of the treatment, PGPpositive rate was 90.2% （strongly-positive, 36.6%） and p53 protein-positive rate was 34.1% （strongly-positive, 19.5%）. In the anthracycline group, the response rate was 40.0%. The number of patients showing poor response to the treatment was significantly larger in the patients with strongly positive PGP expression （P= 0.005）, and their prognoses were poor （P= 0.001）. in the nonanthracycline group, the response rate was 42.9%,and there was no significant relationship between the chemotherapeutic drug efficacy and the PGP or p53 protein expression. When only the data from the 11 patients treated with anthraquinone drug, mitoxantrone, were analyzed, however, the number of patients who showed poor response to treatment was significantly higher among the p53-positive patients （P= 0.012）, irrespective of the survival outcome. CONCLUSION： The chemotherapeutic efficacy with an anthracycline drug for advanced HCC can be predicted by immunohistochemical analysis of PGP expression. Similarly, immunostaining to evaluate p53 protein may be useful to predict the response in patients treated with an anthraquinone drug.

Relationship between P-glycoprotein and CD44 expression in esophageal carcinoma

Objective： To investigate the relationship between P-glycoprotein （P-gp） and adhesion molecule CD44 expression as well as their clinical significance in esophageal carcinoma. Methods： To examine the expressed level of P-gp and CD44 by flow cytometry （FCM） in the operated samples of 70 cases with esophageal carcinoma and their normal mucosa of esophageal incision, and to evaluate their relationship with clinicopathological factors. Results： Among the 70 cases with esophageal carcinoma, the expression of P-gp in the 27 cases （38.6%） was negative （positive cells 〈25%）; 11 cases （15.7%） were 25%-40% expression of P-gp positive cells; 14 cases （20%） were 41%-60% expression of P-gp positive cells; 18 cases （25.7%） were the high expression （positive cells 〉60%） of P-gp. Of the cases with the tumor sizes being more than 4 cm, the expression of CD44 showed a significant difference （P〈0.05） in 25 cases with P-gp positive, compared with 19 cases with P-gp negative. Of the cases with high-mild differentiated esophageal carcinoma, the expression of CD44 showed a significant difference （P〈0.05） in 22 cases with P-gp positive, compared with 17 cases with P-gp negative. Of the cases with clinical Ⅲ-Ⅳ stage, the expression of CD44 showed a significant difference （P〈0.05） in 26 cases with P-gp positive, compared with 10 cases with P-gp negative. Of the cases with lymph node metastasis, the CD44 expression showed a significant difference （P=0.050） in 27 cases with P-gp positive, compared with 11 cases with P-gp negative. Of the cases of the patients＇ age being more than 56 years, the expression of CD44 showed a significant difference （P〈0.01） in 27 cases with P-gp positive, compared with 12 cases with P-gp negative. When the P-gp and CD44 expression were positive, the clinical Ⅱ stage and Ⅲ-Ⅳ stage in esophageal carcinoma was showed a significant difference （P〈0.05）. Conclusion： When the CD44 and P-gp both have the positive high expression, it will be significantly associated with the esophageal carcinoma progression and metastasis, so both were a positive expression in esophageal carcinoma, it might suggest a poor and unfavorable prognosis result.

Identification of the Interaction between P-Glycoprotein and Anxa2 in Multidrug-resistant Human Breast Cancer Cells

Objective To explore the interaction of Anxa2 with P-Glycoprotein （P-gp） in the migration and invasion of the multidrug-resistant （MDR） human breast cancer cell line MCF-7/ADR. Methods A pair of short hairpin RNA （shRNA） targeting P-gp was transfected into MCF-7/ADR cells, and monoclonal cell strains were screened. The expression of P-gp was detected by Western blot. Transwell chambers were used to observe the cell migration capacity and invasion ability. The interaction between P-gp and Anxa2 was examined by immunoprecipitation and immunofluorescence confocal microscopy analyses. Results P-gp expression was significantly knocked down, and there were notable decreasing trends in the migration and invasion capability of MDR breast cancer cells （P〈0.05）. There was a close interaction between Anxa2 and P-gp. Conclusions MCF-7/ADR is an MDR human breast cancer cell line with high migration and invasion abilities. The knockdown of P-gp notably impaired the migration and invasion abilities of the tumor cells. The interaction of Anxa2 with P-pg may play an important role in time enhanced invasiveness of MDR human breast cancer cells.

P-glycoprotein is not involved in pathway of anti-Fas/Fas-induced apoptosis in KBv200 cells

AIM: To verify whether P-glycoprotein (P-gp) could induce cell resistance to apoptosis by inhibiting caspase-8 and caspase-3.METHODS: Human KB cells, either drug-sensitive or with multidrug resistance (MDR) phenotype caused by overexpression of P-gp (KBv200 cells), were treated with anti-Fas (CH-11 monoclonal antibody) to induce apoptosis.Cytotoxicity was detected by MTT assay. Symptoms of cell death were assessed by morphological observation after Hoechst33258 staining, activation of caspase-8 and caspase-3 was measured by Western blotting.RESULTS: Compared with KB cells, the resistance of KBv200 cells to VCR (vincristine) was about 51-fold higher.Anti-Fas (CH-11) induced cytotoxicity and apoptosis in both sensitive KB cells and MDR phenotype KBv200cells. The IC50 of CH-11 in KB cells was similar to that in KBv200 cells. CH-11 induced similar apoptotic rates in both KB cells and KBv200 cells, which could be classified as caspase-dependent apoptotic pathway. Verapamil (VRP) did not affect CH-11-mediated apoptosis in KBv200 cells.CONCLUSION: Expression of P-glycoprotein does not induce resistance to caspase-8 and -3 activation or antiFas-induced cell apoptosis.

P-glycoprotein mediated interactions between Chinese materia medica and pharmaceutical drugs

P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.

REVERSION OF MULTIDRUG RESISTANCE IN THE P-GLYCOPROTEIN POSITIVE BREAST CANCER CELL LINE(MCF-7/ADR) BY INTRODUCTION OF HAMMERHEAD RIBOZYME

A hammerhead ribozyme which site-specifically cleaved the GUC position in canon 880 of the mdr1 mRNA was designed. The target site was chosen between the two ATP binding sites, which may be important for the function of the P-Gp as an ATP-dependent pump. A DNA sequence encoding the ribozyme gene was then incorporated into a eukaryotic expression vector (pH Apr-1 neo) and transfected into the breast cancer cell line MCF-7/Adr, which is resistant to adriamycin and expresses the MDR phenotype. The ribozyme was stably expressed in the cell line by the RNA dot blotting assay. The result of Northern blot assay showed that the expressed ribozyme could decrease the level of mdrl mRNA expression by 83. 5 %; and the expressed ribozyme could inhibite the formation of p-glycoprotein detected by immuno- cy-tochemistry assay and could reduce the cell’s resistance to adrimycin; this means that the resistant cells were 1 000-fold more resistant than the parental cell line(MCF-7), whereas those cell clones that showed ribozyme expression were only 6-fold more resistant than the parental cell line. These results show that a potentially useful tool is at hand which may inactivate MDR1 mRNA and revert the multidrug resistance phenotype.

IMPROVING P-gp EXPRESSION IN HUMAN MONONUCLEAR CELLS IN VITRO TRANSFECTED BY MULTIDRUG RESISTANCE-1 mRNA

Objective To evaluate the expression and function activity of P-glycoprotein (P-gp) in human mononuclear cells (MNCs) in vitro transfected by multidrug resistance-1(MDR1) mRNA. Methods Two MDR1 cDNA vectors, pT7TS_MDR1 and pGEM5Zf(+)_MDR1, were constructed and transcripted in vitro. Vector pGEM5Zf(+)_MDR1 only contained the coding region of mdr1 cDNA, and pT7TS_MDR1 also included Xeponus β-globin 5’ and 3’ untranslated region. MNCs were prepared from peripheral blood of parvicellular lung cancer patient. The two human mdr1 mRNAs were then transferred into human MNCs in vitro by DOTAP. And the expression efficiency and pump function of P-gp were measured with flow cytometry. Results Expression of P-gp significantly elevated in both transferred cells compared with untransferred cells (P < 0.01). And pT7TS_MDR1 showed higher capability in elevating the expression of P-gp than pGEM5Zf(+)_MDR1 (P < 0.01). The P-gp function was elevated in both pT7TS_MDR1 and pGEM5Zf(+)_MDR1 groups. The survival ratio of MNCs in erythrocyte-lysis-solution (ELS, 86.07%) and lymphocyte-isolation-solution (LIS, 83.67%) had no significant difference. The CD34+ cells content of the MNCs used for transfection was 2.65% and 1.01% in ELS and LIS group, respectively (P < 0.01).Conclusions It is a feasible approach to improve P-gp expression in human MNCs by transfection of MDR-1 mRNA. And the ELS may be more suitable for purifing MNCs for mRNA transfection than LIS.

Nude mice multi-drug resistance model of orthotopic transplantation of liver neoplasm and Tc-99m MIBI SPECT on p-glycoprotein

AIM: To establish a model of drug-resistant neoplasms using a nude mice model, orthotopic transplantation of liver neoplasm and sporadic abdominal chemotherapy. METHODS: Hepatocellular carcinoma cells HepG2 were cultured and injected subdermally to form the tumor-supplying mice. The orthotopic drug-resistant tumors were formed by implanting the tumor bits under the envelope of the mice liver and induced by abdominal chemotherapy with Pharmorubicin. Physical examination, ultrasonography, spiral CT and visual inspection were used to examine tumor progression. RT-PCR and immunohistochemistry were used to detect expression of mdr1 mRNA and its encoded protein p-glycoprotein (p-gp). Tc-99m sestamibi scintigraphy was performed by obtaining planar abdominal images at 20 min after injection, and the liver/heart ratios were calculated. RESULTS: Post-implantation mortality was 0% (0/25), tumor implantation success was 90% (22/25), and the rate of implanting successfully for the second time was 100% (3/3). Tumor induction using Pharmorubicin was 80% (16/20). The mdrl mRNA expression of the induced group was 23 times higher than that of the control group, and p-gp protein expression was 13-fold higher compared to the control group. The liver/heart ratio (as assessed in vivo, using Tc-99m radiography) was decreased significantly in the induced group as compared to the control group. CONCLUSION: We have established an in vivo model of mdrl in nude mice by orthotopic transplantation of liver neoplasm coupled to chemotherapy. We propose that identification of drug resistance as characterized by decreased 99mTc-ppm radiography due to enhanced clearance by p-gp may be useful in detecting in vivo drug resistance, as well as a useful tool in designing more effective therapies.

Progress in the expression of P-glycoprotein in brain metastases of lung cancer andrelated TCM research

Brain metastases are common intracranial tumors, and their occurrence not only represents a high degree of malignancy, but also often is the major factor in treatment failure and poor prognosis. Primary site of brain metastases often occur in lung. P-glycoprotein is a member of the （ATP binding cassette） transporter superfamily,which is closely related to the development of lung metastases. It is the main reason for influencing the drug through the blood_brain barrier into the brain tissue, and it also is an important factor affecting the treatment of brain metastases. According to the theory of traditional chinese mddicine, the pathogenesis of brain metastases is due to phlegm, poison, stasis, virtual and so on. The principle of treatment is to promote blood circulation, remove phlegm turbidity. In recent years, the impact of Chinese herbal medicine on P-glycoprotein is increasing. This paper analyzes the mechanism and components of the relevant Chinese medicine on P-glycoprotein. It provides a reference for clinical rational drug use.

Partial characterization of the N-linked oligosaccharide structures on P-selectin glycoprotein ligand-1 (PSGL-1)

PSGL-1, a specific ligand for P-, E- and L-selectin, was isolated from in vivo [3H]-glucosamine labeled HL- 60 cells by a combination of wheat germ agglutinin-agarose and P- or E-selectin-agarose chromatography. N- linked oligosaccharides were released from the purified, denatured ligand molecule by peptide: N-glycosidase F treatment and, following separation by Sephacryl S-200 chromatography, partially characterized using lectin, ion-exchange and size-exclusion chromatography in combination with glycosidase digestions. The data obtained suggest that the N-glycans on PSGL-1 are predominantly core-fucosylated, multiatennary complex type structures with extended, poly- N- acetyllactosamine contaniing outer chains. A portion of the outer chains appears to be substituted with fucose indicating that the N-glycans, in addition to the O-glycans on PSGL-1, may be involved in selectin binding.

缺血性中风抗氧化治疗的临床问题及研究进展

抗氧化剂可以显著降低氧化应激损伤,对缺血性中风具有神经保护作用。然而,抗氧化剂的有效性及副作用问题极大地限制了其临床发展。研究表明,反应氧族(ROS)不仅是缺血性脑损伤的核心因素,而且参与了病后恢复期的组织修复,抗氧化剂的使用障碍可能与ROS复杂的生理作用有关。本文以优化抗氧化剂的使用为目的,阐述缺血性中风后ROS的多重病理生理作用,并对当今抗氧化治疗药物进行综述,通过分析药物运用存在的问题,拟为抗氧化剂基础研究和临床应用提供新的思路。

肺癌细胞的多药耐药性与P53、c-myc、nm23-H_1异常表达关系的探讨

目的 :探讨肺癌细胞的多药耐药性与p5 3、c myc、nm2 3 H1的异常表达的关系。方法 :应用免疫组化技术检测肺癌组织标本中 p gp、p5 3、c myc、nm2 3 H1的表达。结果 :5 8例肺癌组织中 p gp、p5 3、c myc、nm2 3 H1的总阳性率分别为 6 0 .3%、6 8.9%、5 0 %、4 8.3%。其中 p5 3阳性例中 p gp阳性表达 35例 (85 .7% ) ,与mdr 1的表达呈显著正相关 (P <0 .0 5 ) ;c myc阳性例中 p gp阳性表达 17例 (5 8.6 % ) ,与mdr 1的表达无明显相关 (P >0 .0 5 ) ;nm2 3 H1阳性例中 p gp阳性表达 13例 (4 6 .4 % ) ,与mdr 1的表达无明显相关 (P >0 .0 5 )。淋巴结转移阳性组与阴性组p gp阳性表达率为 6 1.3%、4 3.2 % ,与mdr 基因表达无显著相关性 (P >0 .0 5 ) ;各类癌旁组织均可见不同程度的 p gp阳性表达。结论 :肺癌多药耐药基因mdr 1表达受多种基因的调控 ,p5 3过表达可增强mdr 1基因表达 ,c myc、nm2 3 H1过表达及淋巴结转移与否与mdr 1基因表达无明显影响。

Synthesis and reversal effect of a novel N-substituted phthalimidesugar on doxorubicin resistant of human breast cancer cells

Thalidomide （α-N-phthalimido-glutarimide, TLD） is a kind of anti-angiogenic and anti-inflammatory drug, and showed effects in the treatment of several disease entities. In this study, the biological effects of a novel N-sugar substituted phthalimide （STA-35） on the regulation of multidrug resistance （MDR） to doxorubicin （ADR） were investigated. The proliferation of cancer cells was detected by a SRB assay. The activity of P-glycoprotein （P-gp） was determined by a Flow cytometry. The expression of P-gp was measured by western blotting. The results showed that STA-35 inhibited the proliferation of human breast cancer cell line MCF-7 and its ADR resistant cell line MCF-7/ADR, and the relative resistance was only 1.19. Meanwhile, STA-35 could sensitize the cytotoxicity of ADR in MCF-7/ADR cells. In addition, we found that STA-35 reduced the activity of P-gp by suppressing the P-gp expression, which was indicated by the increase in the accumulation of rhodamine 123 in MCF-7/ADR cells. These results suggested a promising application of STA-35 as the MDR reversing agent. The underlying mechanism of the effects might be attributed to the inhibition of P-gp.

The Activity of Erianin and Chrysotoxine from Dendrobium chrysotoxum to Reverse Multidrug Resistance in B16/h MDR-1 Cells

The ability of two dihydrostilbene derivatives erianin and chrysotoxine from Dendrobium chrysotoxum to reverse multidrug resistant (MDR) cells was investigated using murine B16 melanoma cells transfected with the human MDR 1 gene and crossresistant to vinblastine and adriamycin (B16/h MDR 1 cells). Both of the two compounds were shown to increase the accumulation of adriamycin, the P glycoprotein (P gp) substrate, in B16/h MDR 1 transfectants.

Multidrug resistance 1 gene in inflammatory bowel disease: A meta-analysis

The MDR1 gene is an attractive candidate gene for the pathogenesis of inflammatory bowel disease （IBD） and perhaps response to therapy, with evidences at both functional and genetic levels. Its product, the P-glycoprotein （P-gp） functions as a transmembrane efflux pump thus influencing disposition and response of many drugs, some of whom （i.e. glucocorticoids） central to IBD therapy. In addition P-gp is highly expressed in many epithelial surfaces, included gastrointestinal tract （G-I） with a putative role in decreasing the absorption of endogenous or exogenous toxins, and perhaps host-bacteria interaction. Many genetic variations of MDR1 gene has been described and in some instances evidences for different P-gp expression as well drugs metabolism have been provided. However data are often conflicting due to genetic heterogeneity and different methodologies employed. Perhaps the greatest piece of evidence of the physiological importance of P-gp in the G-I tract has come from the description of the mdrl knock-out mice model, which develops a spontaneous colitis in a specific pathogen-free environment. Studies investigating MDR1 gene polymorphism and predisposition to IBD have also shown conflicting results, owing to the known difficulties in complex diseases, especially when the supposed genetic contribution is weak. In this study we have undertaken a metaanalysis of the available findings obtained with two SNPs polymorphism （C3435T and G2677T/A） in IBD; a significant association of 3435T allele and 3435TT genotype has been found with UC （OR = 1.17, P = 0.003 and OR = 1.36, P = 0.017, respectively）. In contrast no association with CD and the G2677T/A polymorphism could be demonstrated.