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Objective A relationship between polymorphisms rs1128503 and rs1045642 in the multidrug resistance 1 gene ( MDR1) and susceptibility to hepatocellular carcinoma (HCC) has been reported but is inconclusive. This study was performed to explore the significance of MDR1 polymorphisms rs1128503 and rs1045642 in screening and diagnosis of HCC. Methods Studies of association analyses between MDR1 gene polymorphisms rs1128503 and rs1045642 and HCC were selected from three foreign language databases (PubMed, Cochrane, and Embase) and three Chinese databases (Wanfang, China National Knowledge Infrastructure, and China Knowledge Network) and subjected to meta-analysis. Results We found no significant relationship between the rs1128503 polymorphism and susceptibility to HCC in 4 cohorts and no significant relationship between the rs1045642 polymorphism and susceptibility to HCC in 3 cohorts. Conclusions There was no relationship between polymorphisms rs1128503 or rs1045642 of the MDR1 gene and susceptibility to HCC.

// Li-liang Xia 1, 4, * , Ya-bin Tang 2, * , Fei-fei Song 2 , Ling Xu 2 , Ping Ji 2 , Shu-jun Wang 2 , Ji-min Zhu 3 , Yong Zhang 2 , Guo-ping Zhao 1, 4, 5 , Ying Wang 2 , Tao-tao Liu 3 1 State Key Laboratory of Genetic Engineering, Department of Microbiology, School of Life Sciences and Institute of Biomedical Sciences, Fudan University, Shanghai, China 2 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China 3 Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China 4 Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China 5 Department of Microbiology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China * These authors have contributed equally to this work Correspondence to: Tao-tao Liu, email: liu.taotao@zs-hospital.sh.cn Li-liang Xia, email: liliangxia@126.com Keywords: dCTP pyrophosphatase 1, chemoresistance to 5-fluorouracil, 5-methyl-dCTP, methylation, multidrug resistance 1 Received: March 31, 2016 Accepted: August 24, 2016 Published: September 06, 2016 ABSTRACT Gastric cancer (GC) is among the most malignant cancers with high incidence and poor prognoses worldwide as well as in China. dCTP pyrophosphatase 1 (DCTPP1) is overexpressed in GC with a poor prognosis. Given chemotherapeutic drugs share similar structures with pyrimidine nucleotides, the role of DCTPP1 in affecting the drug sensitivity in GC remains unclear and is worthy of investigation. In the present study, we reported that DCTPP1- knockdown GC cell line BGC-823 exhibited more sensitivity to 5-fluorouracil (5-FU), demonstrated by the retardation of cell proliferation, the increase in cell apoptosis, cell cycle arrest at S phase and more DNA damages. Multidrug resistance 1 (MDR1) expression was unexpectedly down-regulated in DCTPP1 -knockdown BGC-823 cells together with more intracellular 5-FU accumulation. This was in large achieved by the elevated methylation in promoter region of MDR1 gene. The intracellular 5-methyl-dCTP level increased in DCTPP1- knockdown BGC-823 cells as well. More significantly, the strong correlation of DCTPP1 and MDR1 expression was detectable in clinical GC samples. Our results thus imply a novel mechanism of chemoresistance mediated by the overexpression of DCTPP1 in GC. It is achieved partially through decreasing the concentration of intracellular 5-methyl-dCTP, which in turn results in promoter hypomethylation and hyper-expression of drug resistant gene MDR1 . Our study suggests DCTPP1 as a potential indicative biomarker for the predication of chemoresistance in GC.

P-glycoprotein (P-gp), encoded by the MDR1 (multidrug resistance 1) gene, involves in the efflux of multiple compounds, such as certain antiepileptic drugs. The aim of this research was to observe the impacts of MDR1 (C3435T) variant on the efflux of phenytoin, carbamazepine, valproate, and phenobarbital in vitro. Stable recombinant LLC-PK1 cell systems transfected with MDR1

Several studies have evaluated the association between the multidrug resistance 1 (MDR1) polymorphism (rs1045642 C T) and multiple myeloma (MM). However, the results were not consistent. Therefore, to reach a comprehensive and reliable answer we determined the association of the MDR1 (rs1045642 C T) polymorphism and MM in the context of meta-analysis.All eligible studies published in EMBASE, PubMed, and Web of Science databases before July 2017 were reviewed. Subsequently, to assess the strength of association in the dominant model, recessive model, allelic model, homozygotes contrast, and heterozygotes contrast, pooled odds ratios and 95% confidence intervals (CIs) were calculated by the fixed effects model.A total of four case-control studies with 395 MM cases and 418 healthy controls were included in the meta-analysis. The overall results showed no significant association between the MDR1 (rs1045642 C T) polymorphism and the risk of MM in genetic models (dominant model: OR = 1.04, 95% CI = 0.78-1.38; recessive model: OR = 0.74, 95% CI = 0.52-1.06; allelic model: OR = 0.90, 95% CI = 0.73-1.11; TT vs. CC: OR = 0.80, 95% CI = 0.51-1.25; and CT vs. CC: OR = 1.12, 95% CI = 0.77-1.62). No evidence of publication bias was detected except for the analysis of the recessive model.This meta-analysis suggests that the MDR1 C T polymorphism was not associated with the risk of MM. To confirm these findings, further comprehensive and well-designed studies are needed.

The MDR1 gene encodes for P-glycoprotein (P-gp), which is an efflux transporter at the cell membrane. The P-gp has wide substrate specificity for multiple medications including the lipid lowering drug, atorvastatin. In this study, we investigated the possible association between three common MDR1 gene polymorphisms (G2677T, C3435T, and C1236T), and the lipid lowering effect of atorvastatin among Jordanians. Lipid and lipoproteins were measured in blood samples collected from patients (n = 201) at baseline and during atorvastatin treatment. MDR1 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Both the TT genotype of G2677T and the TT genotype of the C3435T polymorphisms were associated with lower levels of low-density lipoproteins after atorvastatin treatment. However, the effects of atorvastatin on the levels of total cholesterol, triglycerides, and high-density lipoprotein, were not correlated with any of the genotypes in both polymorphisms. Finally, the C1236T polymorphism was not associated with the lipid lowering effect of atorvastatin. In conclusion, the MDR1 gene polymorphisms G2677T, and C3435T, but not C1236T were associated with the lipid lowering effect of atorvastatin among Jordanians.

Drug resistance in chemotherapy is a serious obstacle for the successful treatment of cancer. Drug resistance is caused by various factors, including the overexpression of P‑glycoprotein (P‑gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in vivo and in vitro. In the present study, we investigated whether apigenin is able to reverse drug resistance using adriamycin‑resistant breast cancer cells (MCF‑7/ADR). In our experiments, apigenin significantly decreased cell growth and colony formation in MCF‑7/ADR cells and parental MCF‑7 cells. This growth inhibition was related to the accumulation of cells in the sub‑G0/G1 apoptotic population and an increase in the number of apoptotic cells. Apigenin reduced the mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance‑associated proteins (MRPs) in MCF‑7/ADR cells. Apigenin also downregulated the expression of P‑gp. Apigenin reversed drug efflux from MCF‑7/ADR cells, resulting in rhodamine 123 (Rho123) accumulation. Inhibition of drug resistance by apigenin is related to the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Apigenin decreased STAT3 activation (p‑STAT3) and its nuclear translocation and inhibited the secretion of VEGF and MMP‑9, which are STAT3 target genes. A STAT3 inhibitor, JAK inhibitor I and an HIF‑1α inhibitor decreased cell growth in MCF‑7 and MCF‑7/ADR cells. Taken together, these results demonstrate that apigenin can overcome drug resistance.

We investigated the methylation status of multidrug resistance 1 (MDR1) gene promoter in noncancerous gastric mucosa in relation to gastric cancer (GC) occurrence. Methylation of the MDR1 promoter was estimated in 127 GC and 82 non-GC patients. A significant association was found between higher methylation ratio and occurrence of GC. Higher methylation ratio was also associated with occurrence of GC in both Helicobacter pylori-positive and Helicobacter pylori-negative subjects. Higher MR was also associated with Helicobacter pylori infection. Methylation status of MDR1 gene in noncancerous gastric mucosa would be useful for predicting GC occurrence.

The finding of P. falciparum chloroquine resistance (pfcrt) and P. falciparum multidrug resistance 1(pfmdr1) gene in P. falciparum has become an obstacle in treating malaria. The polymorphism between the two genes may result in molecular functions, in cellular components, or in biological processes. The objective of this research is to find similarities between the two genes in 3 components; cellular components, molecular functions and biological processes, based on Gene Ontology. the similarity will be counted semantically by path length approach with Wang m ethod. The range of similarity values is 0-1. After the similarity value examined; in Molecular Function the similarity is 1 due to the same drug transmembrane transporter activity, in Cellular Component is 0,714, the similarity only at the same vacuole food cells, and in Biological Processes is 1 due to the same proces in responding to drug. Therefore, this research proves both genes have similarities based on gene ontology.

Owing to their role in controlling the efflux of toxic compounds, transporters are central players in the process of detoxification and elimination of xenobiotics, which in turn is related to cancer risk. Among these transporters, ATP-binding cassette B1/multidrug resistance 1 (ABCB1/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP) affect susceptibility to many hematopoietic malignancies. The maintenance of regulated expression of these transporters is governed through the activation of intracellular "xenosensors" like the nuclear receptor 1I2/pregnane X receptor (NR1I2/PXR). SNPs in genes encoding these regulators have also been implicated in the risk of several cancers. Using a tagging approach, we tested the hypothesis that common polymorphisms in the transporter genes ABCB1, ABCC2, ABCG2 and the regulator gene NR1I2 could be implicated in lymphoma risk. We selected 68 SNPs in the four genes, and we genotyped them in 1,481 lymphoma cases and 1,491 controls of the European case-control study (EpiLymph) using the Illumina GoldenGate® assay technology. Carriers of the SNP rs6857600 minor allele in ABCG2 was associated with a decrease in risk of B-cell lymphoma (B-NHL) overall (p < 0.001). Furthermore, a decreased risk of chronic lymphocytic leukemia (CLL) was associated with the ABCG2 rs2231142 variant (p = 0.0004), which could be replicated in an independent population. These results suggest a role for this gene in B-NHL susceptibility, especially for CLL. Copyright © 2011 UICC.

Plasmodium vivax mdr1 gene amplification, quantified by real-time PCR, was significantly more common on the western Thailand border (6 of 66 samples), where mefloquine pressure has been intense, than elsewhere in southeast Asia (3 of 149; P = 0.02). Five coding mutations in pvmdr1 , independent of gene amplification, were also found.

13107 Background: To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and multidrug resistance 1 (MDR1) gene are associated with response to chemotherapy with S-1 in metastatic colorectal cancer. Methods: Eighteen patients with progressive stage IV CRC were treated with S-1 twice daily (BSA = 1.5 m2, 60 mg/day) for 28 days, followed by a 2-week period rest. cDNA was derived from frozen tumor specimens to determine TS and MDR1 mRNA expression relative to the internal reference gene GAPDH using fluorescence-based, real-time reverse transcriptase polymerase chain reaction (Taqman) system. Results: The median TS gene expression level from 18 CRC tumors was 0.94 × 10(−3) (minimum expression, 0.15 × 10(−3); maximum expression, 8.0 × 10(−3)), and the median MDR1 gene expression level was 7.75 × 10(−3) (minimum, 0.83; maximum, 41.5 × 10(−3)). The gene expression cutoff values for chemotherapy nonresponse were 1.0 x 10(-3) for TS and 10.0 × 10(−3) for MDR1. The response rate for patients with TS < or = 1.0 × 10(−3) (10 of 18 patients) was 60% (6/10), compared with 0% (0/8) for patients with TS greater than 1.0 × 10(−3) (P = 0.013). Patients with MDR1 expression < or = 10.0 × 10(−3) (13 of 18 patients) had a response rate of 46% (6/13), compared with 0% (0/5) for patients with MDR1 expression greater than 10.0 × 10(−3) (P = 0.11). Regarding the combination of TS and MDR1 Expression, low TS and MDR1 expression levels were detected in 8 (44%) of the patients, and 10 patients (56%) had a high TS and/or MDR1 expression level. The response rate was 75% (6/8) for the low TS and MDR1 expressors and 0% (0/10) for the high TS and/or MDR1 expressors (P = 0.001). Conclusions: These data suggest that intratumoral TS and MDR1 mRNA expression levels are independent predictive markers of response to S-1 chemotherapy in metastatic colorectal cancer. No significant financial relationships to disclose.