• Humans
• ATP Binding Cassette Transporter, Subfamily B/genetics
• ATP Binding Cassette Transporter, Subfamily B/metabolism
• ATP Binding Cassette Transporter, Subfamily B/chemistry
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Polymorphism, Single Nucleotide/genetics
• Neoplasms/genetics
• Neoplasms/metabolism
• Computational Biology
• RNA Folding/genetics
• ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Gene Expression Regulation, Neoplastic

• genetics research
• cancer genomics

• Humans
• Imatinib Mesylate/therapeutic use
• Prognosis
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
• Antineoplastic Agents/adverse effects
• Protein Kinase Inhibitors/therapeutic use
• Membrane Transport Proteins/therapeutic use
• Treatment Outcome

• 00023736 Ministerstvo Zdravotnictví Ceské Republiky (Ministry of Health of the Czech Republic)
• NCN 2018/31/B/NZ6/03361 Narodowe Centrum Nauki (National Science Centre)

• ABCB1
• ABCG2
• Chronic myeloid leukemia
• Complete cytogenetic response
• Imatinib mesylate
• Smoke

• chronic myeloid leukemia
• imatinib
• major molecular response
• single-nucleotide polymorphisms

• ADME
• Imatinib
• Pharmacogenetics
• Pharmacokinetics
• Population pharmacokinetics

• ABCB1
• Acute lymphoblastic leukemia
• BCR-ABL1
• Chronic myeloid leukemia
• Kashmir
• RFLP

• Chronic myeloid leukemia
• imatinib mesylate
• multidrug resistance gene
• polymorphisms

Metabolic reprogramming of tumour cells sustains cancer progression. Similar to other cancer cells, glioblastoma cells exhibit an increased glycolytic flow, which encourages the use of antiglycolytics as an effective complementary therapy. We used the antiglycolytic 3-bromopyruvate (3BP) as a metabolic modifier to treat U118 glioblastoma cells and investigated the toxic effects and the conditions to increase drug effectiveness at the lowest concentration. Cellular vitality was not affected by 3BP concentrations lower than 40 μM, although p-Akt dephosphorylation, p53 degradation, and ATP reduction occurred already at 30 μM 3BP. ROS generated in mitochondria were enhanced at 30 μM 3BP, possibly by unbalancing their generation and their disposal because of glutathione peroxidase inhibition. ROS triggered JNK and ERK phosphorylation, and cyt c release outside mitochondria, not accompanied by caspases-9 and -3 activation, probably due to 3BP-dependent alkylation of cysteine residues at caspase-9 catalytic site. To explore the possibility of sensitizing cells to 3BP treatment, we exploited 3BP effects on mitochondria by using 30 μM 3BP in association with antimycin A or menadione concentrations that in themselves exhibit poor toxicity. 3BP effect on cyt c release and cell vitality loss was potentiated due the greater oxidative stress induced by antimycin or menadione association with 3BP, supporting a preeminent role of mitochondrial ROS in 3BP toxicity. Indeed, the scavenger of mitochondrial superoxide MitoTEMPO counteracted 3BP-induced cyt c release and weakened the potentiating effect of 3BP/antimycin association. In conclusion, the biochemical mechanisms leading U118 glioblastoma cells to viability loss following 3BP treatment rely on mitochondrial ROS-dependent pathways. Their potentiation at low 3BP concentrations is consistent with the goal to minimize the toxic effect of the drug towards non-cancer cells.

• 3-Bromopyruvate
• Antimycin A
• Biochemistry
• Biological sciences
• Cancer research
• Cytochrome c
• Glioblastoma cells
• Menadione
• Mitochondrial ROS
• Oxidative stress

• Codon Usage
• Databases, Genetic
• Genetics, Population
• Genome-Wide Association Study
• Humans
• Web Browser

• RF1 AG054052 NIA NIH HHS
• National Institute on Aging

IM, a strong and selective TKI, has been approved as the front line of treatment in CML patients. In spite of satisfactory results of imatinib in the treatment of patients with CML, patients with treatment failure or suboptimal response developed resistance that might be because of pharmacogenetic variants. This study attempted to evaluate the influence of ABCB1 gene polymorphisms and smoking on CML risk and resistance to imatinib.

ABCB1 (c.1236C>T, c.3435C>T) polymorphisms were genotyped in 98 CML patients and 100 sex- and age-matched healthy subjects by PCR-RFLP method, followed by sequencing. The patients were evaluated for cytogenetic response by the standard chromosome banding analysis in regular intervals.

Our results showed that c.1236CC genotype was significantly associated with imatinib resistance (OR = 3.94; p = 0.038). Analysis of the joint of SNP-smoking combination showed that smokers with c.1236TT/CT and c.1236CC genotypes had the increased risk of CML (OR = 6.04; p = 0.00 and OR = 4.95, p = 0.005) and treatment failure (OR = 5.36, p = 0.001 and OR = 15.7, p = 0.002), respectively. Smokers with c.3435TT/CT and c.3435CC genotypes also displayed the elevated risk of CML development (OR = 6.01, p = 0 and OR = 4.36, p = 0.011) and IM resistance (OR = 5.61, p = 0.001 and OR = 13.58, p = 0.002), respectively.

Our findings suggest that c.1236CC genotype has clinical importance in the prediction of treatment outcome with IM, and smoking could have a synergistic role in CML risk and IM resistance.

• ATP binding cassette transporter subfamily B
• Imatinib mesylate
• Smoking

Purpose: Polymorphisms of genes in the platelet-derived growth factor (PDGF) signaling pathway have been found to predict cutaneous melanoma (CM) survival, but their clinical effects in acral melanoma (AM) patients have not been explored. The aim of this study was to characterize the functional effect of the tag single-nucleotide polymorphism (SNP) rs2228230:C>T and assess its association with clinical outcomes in AM patients.

Methods: The effect of rs2228230:C>T on mRNA structures and codon usage values were evaluated using in silico analyses. PDGF receptor alpha (PDGFRA) expression vectors with the rs2228230:C or rs2228230:T allele were constructed to evaluate the expression and signaling activity of PDGFRA. The expression of PDGFRA in AM samples was measured using in situ RNAscope hybridization and immunohistochemical staining. The association of the rs2228230 genotype with survival was analyzed in two independent AM cohorts.

Results: In silico analyses indicated that the rs2228230:T allele increases the minimum free energy and reduces synonymous codon usage. The rs2228230:T allele decreased the expression of PDGFRA by reducing the stability of its mRNA and protein as well as the signaling activity of the MAPK and PI3K/AKT pathways. PDGFRA mRNA and protein expression was significantly reduced in AM tissues with the rs2228230:T allele. The progression-free survival and overall survival of AM patients with the rs2228230:T allele were significantly longer than those of patients with the CC genotype.

Conclusion: Our study indicated that rs2228230:T can reduce the expression of PDGFRA and downstream signaling activity and is associated with better survival in AM patients.

• PDGFRA
• acral melanoma
• gene expression regulation
• genetic variation
• survival

Imatinib is the first-line drug used for the treatment of chronic myeloid leukemia (CML) patients due to high molecular response and overall survival rate. However, some patients develop resistance to imatinib even after attaining a response. Mutation in ABCB1 efflux transporters is one of the known mechanisms of resistance to imatinib in chronic myeloid leukemia patients. This study was aimed to investigate the association of ABCB1 C1236T polymorphism in Indonesian chronic myeloid patients with molecular response to imatinib treatment.

We analyzed 120 samples from chronic myeloid leukemia patients in the chronic phase, who had been on imatinib treatment for at least 12 months. We analyzed the C1236T variant of the ABCB1 gene using PCR, followed by direct sequencing, and associate them with the achievement of major molecular response (MMR).

The major molecular response was achieved in 28% of patients. The frequencies of the SNPs were CC (40%), CT (46%), and TT (14%). Our result showed that there was a lack of association between polymorphism of ABCB1 C1236T and imatinib response in Indonesian patients, with OR = 0.646 (95% CI: 0.283, 1.471; p>0.05).

There was no association between ABCB1 C1236T variants with the major molecular response in Indonesian chronic myeloid leukemia patients receiving imatinib treatment.

• ABCB1
• C1236T
• Chronic myeloid leukemia
• imatinib

Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1-1222AA carriers. Patients with the ABCG2-34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1-2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13–65 years of age.

• Chinese
• NONMEM
• epilepsy
• lamotrigine
• population pharmacokinetics

• P-glycoprotein
• chronic myeloid leukemia
• drug resistance
• inhibitor apoptosis proteins
• microRNAs
• microvesicles
• new compounds
• tyrosine kinase inhibitor

• ATP Binding Cassette Transporter, Subfamily B/physiology
• Animals
• Drug Resistance, Neoplasm
• Genetic Predisposition to Disease
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
• Polymorphism, Single Nucleotide
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use

• Chronic myeloid leukemia
• Mechanisms of TKI resistance
• Tyrosine kinase inhibitors

• Drug Resistance, Neoplasm
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Molecular Targeted Therapy
• Mutation
• Protein Kinase Inhibitors/pharmacology

• GIST
• Imatinib
• Pharmacogenetic pathway analysis
• SNPs
• Survival
• VEGF

• ABCB1
• Chronic myeloid leukemia
• Haplotypes
• Imatinib mesylate
• Polymorphisms
• Resistance
• mRNA expression

• BCR-ABL1
• Chronic myeloid leukemia (CML)
• Drug resistance
• Mutation
• Treatment-free remission (TFR)
• Tyrosine kinase inhibitor (TKI)

• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biological Availability
• Biomarkers
• Cell Survival/drug effects
• Cell Survival/genetics
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Resistance, Neoplasm/genetics
• Fusion Proteins, bcr-abl/antagonists & inhibitors
• Fusion Proteins, bcr-abl/chemistry
• Fusion Proteins, bcr-abl/genetics
• Gene Expression Regulation, Leukemic/drug effects
• Humans
• Immunotherapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
• Models, Molecular
• Molecular Targeted Therapy
• Mutation
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Signal Transduction/drug effects
• Structure-Activity Relationship

• R01 CA178397 NCI NIH HHS
• R21 CA205936 NCI NIH HHS

• ABCB1 polymorphisms
• chemotherapy response
• leukemia
• survival

Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia.

In silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher’s exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression.

We observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers.

This exploratory study depicted potentially important genetic markers predicting outcome of imatinib treatment, which may be helpful for tailoring therapy in clinical practice.

The online version of this article (doi:10.1186/s13046-017-0523-3) contains supplementary material, which is available to authorized users.

• CML
• Imatinib
• Response
• SLC

• Imatinib resistance
• P-glycoprotein
• Personalized medicine
• Pharmacogenetics
• Single nucleotide polymorphisms
• Tyrosine kinase inhibitor

• ABCB1
• ABCG2
• clinical response
• imatinib
• meta-analysis
• polymorphism
• trough concentration

• ABC transporters
• SLC transporters
• clinical trials
• drug resistance
• interindividual variability
• pharmacogenomics
• tyrosine kinase inhibitors

• ATP Binding Cassette Transporter, Subfamily B/genetics
• ATP Binding Cassette Transporter, Subfamily B/metabolism
• Humans
• Pharmacokinetics
• Polymorphism, Single Nucleotide
• Xenobiotics/pharmacokinetics

• ABCB1
• BCR-ABL
• CML
• SNPs
• TKIs

Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed.

• bosutinib
• chronic myeloid leukemia
• dasatinib
• imatinib
• nilotinib
• pharmacogenetics
• pharmacogenomics
• ponatinib
• transmembrane transporter

• ATP-Binding Cassette Transporters/genetics
• ATP-Binding Cassette Transporters/metabolism
• Animals
• Biological Transport
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl/antagonists & inhibitors
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
• Organic Cation Transport Proteins/genetics
• Organic Cation Transport Proteins/metabolism
• Pharmacogenetics
• Protein Kinase Inhibitors/pharmacokinetics
• Protein Kinase Inhibitors/pharmacology

AIM: To evaluate the correlations between cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and multi-drug resistance 1 (MDR1) genes polymorphisms with ulcerative colitis (UC) risk.

METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, CBM databases, Springerlink, Wiley, EBSCO, Ovid, Wanfang database, VIP database, China National Knowledge Infrastructure, and Weipu Journal databases were exhaustively searched using combinations of keywords relating to CTLA-4, MDR1 and UC. The published studies were filtered using our stringent inclusion and exclusion criteria, the quality assessment for each eligible study was conducted using Critical Appraisal Skill Program and the resultant high-quality data from final selected studies were analyzed using Comprehensive Meta-analysis 2.0 (CMA 2.0) software. The correlations between SNPs of CTLA-4 gene, MDR1 gene and the risk of UC were evaluated by OR at 95%CI. Z test was carried out to evaluate the significance of overall effect values. Cochran’s Q-statistic and I² tests were applied to quantify heterogeneity among studies. Funnel plots, classic fail-safe N and Egger’s linear regression test were inspected for indication of publication bias.

RESULTS: A total of 107 studies were initially retrieved and 12 studies were eventually selected for meta-analysis. These 12 case-control studies involved 1860 UC patients and 2663 healthy controls. Our major result revealed that single nucleotide polymorphisms (SNPs) of CTLA-4 gene rs3087243 G > A and rs231775 G > A may increase the risk of UC (rs3087243 G > A: allele model: OR = 1.365, 95%CI: 1.023-1.822, P = 0.035; dominant model: OR = 1.569, 95%CI: 1.269-1.940, P < 0.001; rs231775 G > A: allele model: OR = 1.583, 95%CI: = 1.306-1.918, P < 0.001; dominant model: OR = 1.805, 95%CI: 1.393-2.340, P < 0.001). In addition, based on our result, SNPs of MDR1 gene rs1045642 C > T might also confer a significant increases for the risk of UC (allele model: OR = 1.389, 95%CI: 1.214-1.590, P < 0.001; dominant model: OR = 1.518, 95%CI: 1.222-1.886, P < 0.001).

CONCLUSION: CTLA-4 gene rs3087243 G > A and rs231775 G > A, and MDR1 gene rs1045642 C > T might confer an increase for UC risk.

• Ulcerative colitis
• Cytotoxic T lymphocyte-associated antigen-4
• Multi-drug resistance 1
• rs3087243 G > A
• rs231775 G > A
• rs1045642 C > T
• Polymorphism
• Meta-analysis

• ATP Binding Cassette Transporter, Subfamily B/genetics
• CTLA-4 Antigen/genetics
• Case-Control Studies
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/genetics
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Linear Models
• Odds Ratio
• Phenotype
• Polymorphism, Single Nucleotide
• Risk Assessment
• Risk Factors

• Chronic myelogenous leukemia
• MRP1
• Multidrug resistance
• P-glycoprotein
• Rhodamine-123 efflux assay

• ATP-binding cassette subfamily B member 1
• Acute leukemia
• Adult
• Efficacy
• High-dose methotrexate
• Methotrexate
• Serum concentration
• Single nucleotide polymorphism

• haematology
• imatinib
• pharmacodynamics
• pharmacokinetics
• rituximab

P-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound.

The in vitro and in vivo activity was determined using the MTT assay and human breast cancer xenograft models. The gene and protein expression of P-glycoprotein were determined using real-time polymerase chain reaction and the Western blotting technique, respectively. ABCB-1 bioactivity was tested by fluorescence microscopy, multi-mode microplate reader, and flow cytometry. The intracellular levels of ATP, HK-II, and ATPase activity were based on an assay kit according to the manufacturer’s instructions.

3-Bromopyruvate treatment led to marked decreases in the IC₅₀ values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased. Furthermore, we found that the mRNA and the total protein level of P-glycoprotein were slightly altered by 3-Bromopyruvate. Moreover, the ATPase activity was significantly inhibited when 3-Bromopyruvate was applied.

We demonstrated that 3-Bromopyruvate can reverse P-glycoprotein-mediated efflux in MCF-7/ADR cells. Multidrug resistance reversal by 3-Bromopyruvate occurred through at least three approaches, namely, a decrease in the intracellular level of ATP and HK-II bioactivity, the inhibition of ATPase activity, and the slight decrease in P-glycoprotein expression in MCF-7/ADR cells.

• ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors
• ATP Binding Cassette Transporter, Subfamily B/metabolism
• Animals
• Antineoplastic Agents/pharmacology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Breast Neoplasms/mortality
• Cell Line, Tumor
• Drug Resistance, Multiple/drug effects
• Drug Resistance, Neoplasm/drug effects
• Enzyme Inhibitors/pharmacology
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/metabolism
• Pyruvates/pharmacology
• Xenograft Model Antitumor Assays

• ATP Binding Cassette Transporter, Subfamily B/genetics
• Adult
• Aged
• Antineoplastic Agents/therapeutic use
• Benzamides/therapeutic use
• Cohort Studies
• Egypt/epidemiology
• Female
• Haplotypes/genetics
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
• Male
• Middle Aged
• Piperazines/therapeutic use
• Polymorphism, Single Nucleotide/genetics
• Predictive Value of Tests
• Pyrimidines/therapeutic use
• Retrospective Studies
• Treatment Failure
• Treatment Outcome
• Young Adult

• ABCB1
• LRPPRC
• chronic myeloid leukemia
• methylation
• multidrug resistance