FRAX486, a PAK inhibitor, overcomes ABCB1-mediated multidrug resistance in breast cancer cells

The overexpression of P-glycoprotein (P-gp/ABCB1) is a leading cause of multidrug resistance (MDR). Hence, it is crucial to discover effective pharmaceuticals that counteract ABCB1-mediated multidrug resistance. FRAX486 is a p21-activated kinase (PAK) inhibitor. The objective of this study was to investigate whether FRAX486 can reverse ABCB1-mediated multidrug resistance, while also exploring its mechanism of action. The CCK8 assay demonstrated that FRAX486 significantly reversed ABCB1-mediated multidrug resistance. Furthermore, western blotting and immunofluorescence experiments revealed that FRAX486 had no impact on expression level and intracellular localization of ABCB1. Notably, FRAX486 was found to enhance intracellular drug accumulation and reduce efflux, resulting in the reversal of multidrug resistance. Docking analysis also indicated a strong affinity between FRAX486 and ABCB1. This study highlights the ability of FRAX486 to reverse ABCB1-mediated multidrug resistance and provides valuable insights for its clinical application.

Meta-analysis of the effects of ABCB1 genotype on the efficacy and safety of taxanes in the treatment of breast cancer / 中国药房

OBJECTIVE To evaluate the effects of ABCB1 genotypes on the efficacy and safety of taxanes in the treatment of breast cancer. METHODS By searching Embase，the Cochrane Library， PubMed， CNKI， and Wanfang databases， cohort studies and case-control studies about taxanes in the treatment of breast cancer were collected from the establishment of the database to July 2023. After screeningliterature， extracting data and evaluating quality， meta-analysis was performed by using RevMan 5.3 software. RESULTS A total of 11 studies were included， involving 1 321 patients. There was no correlation between the three genotypes and effective rate， the incidence of myelosuppression， the incidence of neurotoxicity （except for the allele and recessive model of ABCB1 C1236T）， and the incidence of hypersensitivity reactions （P＞0.05）. The subgroup analysis showed that there was a correlation between ABCB1 C1236T dominant model and effective rate when using anthracyclines+5-fluorouracil+cyclophosphamide+taxanes （P＜0.05）， there was a correlation between ABCB1 C3435T recessive model and effective rate when using taxanes+trastuzumab （P＜0.05）. ABCB1 C1236T allele model and recessive model were correlated with sample size ≥100 and using cyclophosphamide+epirubicin+5- fluorouracil+paclitaxel or cyclophosphamide+epirubicin+paclitaxel+trastuzumab or cyclophosphamide+epirubicin+5-fluorouracil+ trastuzumab+paclitaxel regimens； recessive model with sample size ＜100 and the African region were correlated with the incidence of peripheral neuropathy； recessive model was correlated with cutaneous adverse reactions （P＜0.05）. ABCB1 C3435T recessive model was correlated with the incidence of reduced neutrophil count with sample size ≥100； the incidence of white blood cell count reduction with sample size ＜100 and using docetaxel+epirubicin+cyclophosphamide was correlated with both the allele model and the dominant model； the incidence of infections was correlated with the dominant model （P＜0.05）. The incidence of neutrophil count reduction with the sample size ＜100 was correlated with allele model of ABCB1 G2677T/A； the incidence of edema with sample size ≥100 was correlated with allele model and recessive model； the incidence of infection was correlated with allele model and dominant model， especially in patients with neutrophil count complicated with fever （P＜0.05）. CONCLUSIONS ABCB1 genotypes are not correlated with effective rate of taxanes in the treatment of breast cancer， but ABCB1 C3435T genotype is associated with decreased neutrophil counts， decreased white blood cell counts and infections； ABCB1 C1236T genotype is associated with neurotoxicity and cutaneous adverse reactions； ABCB1 G2677T/A genotype is associated with decreased neutrophil counts， infections， and edema.

Effects of C3435T polymorphism in ABCB1 gene on lipid-lowering efficacy of statins：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the effects of C3435T polymorphism in ABCB1 gene on lipid-lowering efficacy of statins. METHODS Retrieved from PubMed， Web of Science， the Cochrane Library， CNKI and VIP， the cohort studies on the use of statins were collected from the inception to November 1， 2023. After literature screening， data extraction and quality evaluation， meta-analysis was performed by using RevMan 5.4 software. RESULTS A total of 11 literature involving 1 575 patients were included. The results showed that under the dominant genetic model， the reduction of low-density lipoprotein cholesterol （LDL-C） [MD＝－1.87， 95%CI （－3.62， －0.13）， P＝0.04]， total cholesterol （TC） [MD＝－1.42， 95%CI （－2.80， －0.04）， P＝0.04] in patients with CT+TT genotype was significantly higher than CC genotype. There was no significant difference in the increase of high-density lipoprotein cholesterol （HDL-C） [MD＝－0.65， 95%CI （－2.48， 1.18）， P＝0.49] or the decrease of triglyceride （TG） [MD＝－0.05， 95%CI （－2.94， 2.84）， P＝0.97] between patients with CT+TT genotype and CC genotype. Under the recessive genetic model， the reduction of TC [MD＝2.26， 95%CI （0.97， 3.56）， P＝0.000 6] and the increase of HDL-C [MD＝2.38， 95%CI （0.42， 4.35）， P＝0.02] in patients with TT genotype were significantly higher than CC+ CT genotype. There was no significant difference in the reduction of LDL-C [MD＝1.53， 95%CI （－0.10， 3.15）， P＝0.07] or TG [MD＝0.06， 95%CI （－2.98， 3.10）， P＝0.97] between CC+CT genotype and TT genotype. Under the additive genetic model， the reduction of TC [MD＝2.98， 95%CI （1.27， 4.69）， P＝0.000 6] and LDL-C [MD＝2.84， 95%CI （0.67， 5.01）， P＝0.01] in patients with TT genotype were significantly higher than CC genotype. There was no significant difference in the increase of HDL-C [MD＝2.40， 95%CI （－0.17， 4.97）， P＝0.07] or the decrease of TG [MD＝0.97， 95%CI 　　 （－2.93， 4.87）， P＝0.63] between patients with TT genotype and CC genotype. CONCLUSIONS The reduction of LDL-C and TC in patients with dyslipidemia treated with statins may be related to the heterozygous and homozygous mutation of C3435T in ABCB1 gene， and the reduction of LDL-C and TC in patients with CT or TT genotype is more obvious， compared with patients with CC genotype. The elevation of HDL-C may be related to homozygous mutation， and the effect of HDL-C elevation may be more obvious in patients with TT genotype， compared with CC+CT genotype. However， the change of TG may not be related to the C3435T polymorphism in ABCB1 gene.

Interpretation of results obtained using real-time fluorescence PCR based on multiplex PCR fragment analysis for ABCB1 tri-allele / 四川精神卫生

ObjectiveTo resolve the problems related to the abnormal interpretations of real-time fluorescence polymerase chain reaction （PCR） results for tri-allele， to formulate the interpretation methods of real-time fluorescence PCR by referring to multiplex PCR fragment analysis， so as to obtain an accurate， simple and cheap detection method for ABCB1 tri-allele. MethodsA total of 2 794 DNA samples were collected from Xi'an Mental Health Center from March 2020 to March 2021， and 5% of which were selected as experiments. Real-time fluorescence PCR method and multiplex PCR fragment analysis method were performed respectively. According to the comparison of Ct values of PCR curves and the comparison of base peak intensity in multiplex PCR fragment analysis， comparison and analysis were conducted on the interpretation results of the two methods， and samples with different interpretation results were verified， thereafter， PCR interpretation method was formulated. ResultsA total of 139 samples were collected， of which 120 alleles and 19 tri-allele were detected. The results of allele detection by two methods were absolutely consistent. In combination with the results of multiplex PCR fragment analysis， a method for the interpretation of real-time fluorescence PCR for 19 cases of tri-allele was developed as follows： when ∣∣Ct.G－Ct.T∣－∣Ct.G－Ct.A∣∣ in amplification curve was less than 3， the interpretation results were the combination of the base pairs with small Ct values； when ∣∣Ct.G－Ct.T∣－∣Ct.G－Ct.A∣∣ was greater than or equal to 3， the interpretation results were homozygotes from the base pairs with minimum Ct values. According to the interpretation method， the results of real-time fluorescence PCR were revised， and it showed 1 case of G/G， 1 case of A/A， 4 cases of T/G， 5 cases of T/A and 8 cases of T/T， which were consistent with the results of multiplex PCR fragment analysis. ConclusionReferring to the multiplex PCR fragment analysis method， the interpretation of ABCB1 tri-allele by real-time fluorescence PCR is developed， and the two interpretation methods are in good agreement.

Skin photosensitivity induced by Voriconazole in children with ABCB1 rs1045642 T/T genotype: a case report and literature review / 中华实用儿科临床杂志

The clinical data of a child with ABCB1 rs1045642 T/T genotype and skin photosensitivity induced by Voriconazole were analyzed retrospectively in Beijing Children′s Hospital, Capital Medical University in September 2020.Literature was reviewed to discuss the relationship between ABCB1 genetic polymorphism and Voriconazole pharmacokinetics.The patient was a 6.8-year-old boy, who was diagnosed with primary immunodeficiency disease.Long-term oral Voriconazole was administered for prevention and treatment of fungal infections.Skin photodistributed erythema and pigmentation occurred about 3-4 weeks after treatment.The skin lesions were significantly alleviated about 1 month after the withdrawal of Voriconazole.Gene test showed ABCB1 rs1045642 T/T in the patient.Some studies reported that ABCB1 rs1045642 T/T genotype reduced the clearance rate of Voriconazole.Monitoring such adverse reaction of Voriconazole in clinical practice is important. ABCB1 gene polymorphism is possible to correlate with the pharmacokinetics and adverse reactions of Voriconazole.However, further large-scale clinical studies are warranted to verify it.

Effect of Notoginseng Total Saponins on Changing Multidrug Resistance in HepG2/ Adriamycin Cells Through ERK/Akt Signaling / 中国实验方剂学杂志

Objective:To investigate the effect of notoginseng total saponins （TNS） on adriamycin （Adr） resistance in HepG2/Adr cells and the expression and activity of the mechanisms as the modulators of multi-drug resistance， so as to explore the possible mechanism of extracellular signal-regulated kinase （ERK） and protein kinase B （Akt） signaling pathways in reversing the resistance of HepG2/Adr cells mechanism. Method:Effect of TNS on HepG2/Adr cell proliferation was detected by thiazole blue （MTT） method. HepG2/Adr cells were treated with different concentrations （100， 50， 25， 0 mg·L^-1） of TNS and （20 μmol·L^-1） Adr respectively， and a blank group was set. The high-content screening platform was used to detect the accumulation of Adr in HepG2/Adr cells after 40 minutes， 3 hours and 6 hours. Western blot was used to detect the expression of P-glycoprotein /multidrug resistance/ATP binding cassette subfamily B member 1（P-gp/MDR1/ABCB1） and other drug resistance-related proteins and the main protein expression of ERK/Akt signaling pathway. The change of MDR1 on cell membranes was observed by laser confocal microscopy. Result:Compared with HepG2 cells， the expression of MDR1 in HepG2/Adr cells was significantly increased （<italic>P</italic><0.01）. Compared with the Adr group， the half-inhibitory concentration （IC₅₀） of TNS （25， 50， 100 mg·L^-1） and Adr （20 μmol·L^-1） co-administration group on HepG2/Adr cells <italic>in vitro</italic> significantly reduced （<italic>P</italic><0.01）， and the highest reversal multiple was 10 times. Compared with the Adr group， the co-administration group could significantly increase the accumulation of Adr in the cells （<italic>P</italic><0.05） in a dose-dependent manner. Compared with the blank group， the co-administration group could significantly reduce MDR1， ABC semitransporter （ABCG2）， multidrug resistance associated protein （MRP1）， ERK， phosphorylated extracellular regulatory protein kinase （p-ERK）， Akt， phosphorylated protein kinase B （p-Akt）， mammals， rapamycin target protein （mTOR） and phosphorylated mammalian rapamycin target protein （p-mTOR） （<italic>P</italic><0.05）， with the same results in the doxorubicin group. Compared with the blank group， there was no significant difference in the distribution and fluorescence intensity of MDR1 on the cell membrane between the Adr group and the notoginseng total saponins （25 mg·L^-1） group. Compared with the blank group and the doxorubicin group， TNS could significantly reduce the distribution of MDR1 on the cell membrane （<italic>P</italic><0.05）. Conclusion:TNS can inhibit the ERK/Akt pathway， reduce the expression of MDR1， and significantly increase the accumulation of doxorubicin in HepG2/Adr cells， which may be one of the mechanisms of notoginseng total saponins in reversing resistance.

Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy

Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of

First report of nt230(del4) mutation in the MDR1 gene in German Shepherds in Southern Brazil / Primeiro relato da mutação nt230(del4) no gene MDR1 em Pastores Alemães no Sul do Brasil

ABSTRACT: The P-glycoprotein (P-gp) is a transmembrane protein encoded by the MDR1 gene that functions as a biological barrier by extruding toxins and xenobiotics out of cells. The MDR1 gene can carry a mutation called nt230(del4), which is a deletion of four base pairs resulting in the formation of a non-functional protein that may predispose to severe toxicosis, as observed in dogs with sensitivity to ivermectin. Several breeds have been described as carriers of the mutation, including German Shepherds (GS). However, the presence of the mutant allele in this breed has not been described in Brazil. This study aimed to determine the genotypic and allelic frequency of the nt230(del4) mutation in the MDR1 gene in GS from Southern Brazil. Blood samples were collected from 79 GS in the state of Rio Grande do Sul and genotype for the MDR1 gene was performed. Seventy-eight (98.7%) dogs were dominant homozygous genotype (wild) and one (1.3%) was heterozygous. This study showed that there is a low frequency (0.6%) of the mutant allele while the frequency of the wild allele is high (99.4%) in this specific population. This is the first report of the presence of the nt230(del4) mutation in the MDR1 gene in GS in Brazil. This information is important for breeders to prevent dissemination of the mutant allele in the national breeding population and international exchange of animals for breeding; for owners and veterinarians to be aware when dispensing and administering medications for GS dogs in Brazil.

RESUMO: A Glicoproteína-P é uma proteína transmembrana codificada pelo gene MDR1 que atua como uma barreira fisiológica através da extrusão de toxinas e xenobióticos para fora das células. O gene MDR1 pode carregar uma mutação chamada nt230(del4) que é uma deleção de quatro pares de bases, resultando na formação de uma proteína não-funcional que pode predispor à toxicoses graves, como as observadas em cães sensíveis à ivermectina. Diversas raças de cães foram descritas como portadoras da mutação nt230(del4), incluindo Pastores Alemães (PA). Entretanto, a presença do alelo mutante nessa raça não foi descrita em cães no Brasil. O objetivo desse estudo foi determinar a frequência genotípica e alélica da mutação nt230(del4) em PA no sul do Brasil. Amostras de sangue foram coletadas de 79 PA no estado do Rio Grande do Sul e o genótipo dos cães para o gene MDR1 realizado. Setenta e oito (98.7%) cães foram homozigotos dominantes (selvagem) e um (1.3%) tinha genótipo heterozigoto. A frequência do alelo mutante foi baixa (0.6%), enquanto a frequência do alelo selvagem foi alta (99.4%) nesta população. Este é o primeiro relato da presença desta mutação nt230(del4) no gene MDR1 em PA no Brasil. Esta informação é importante para criadores a fim de prevenir a disseminação do alelo mutante na população de criadores da raça no Brasil e programas internacionais de troca de animais para criação, para tutores e veterinários estarem conscientes quando prescreverem e administrarem medicações para cães PA no Brasil.

Relationship between Multidrug Resistance Gene ABCB1 C3435T Gene Polymorphism and Serum Concentration of Levetiracetam in Children with Epilepsy in Xinjiang / 中国药学杂志

OBJECTIVEP: To explore the relationship between multidrug resistance gene ABCB1 C3435T gene polymorphism and serum concentration, clinical efficacy and adverse reactions of levetiracetam (LEV) in children with epilepsy in Xinjiang. METHODS: The serum concentration of 116 children with epilepsy of in Xinjiang were collected and determined by oral LEV. The ABCB1 C3435T genotype was detected by polymerase chain reaction-fluorescence staining in situ hybridization. The correlation between ABCB1 C3435T gene polymorphism and serum concentration, clinical efficacy and adverse reactions was analyzed. RESULTS: The C and T allele frequencies of ABCB1 C3435T in children were significantly different (χ2=12.520, P0.05). The clinical effective rate of CT type was higher than that of CC type and TT type, and the incidence of adverse reactions of TT type was higher than that of CC type and CT type. There were significant differences in clinical efficacy and adverse reactions among CC type, CT type and TT type (χ2=12.870,P<0.01; χ2=19.292, P<0.01). CONCLUSION: ABCB1 C3435T gene polymorphism may has a effect on the serum concentration, clinical efficacy and adverse reactions of LEV in children with epilepsy in Xinjiang.

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells and o

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

Effect of ABCB1 3435C>T transporter gene polymorphism on plasma efavirenz concentration in HIV-1 infected Thai adults

Objective: To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1. Methods: A single nucleotide polymorphism of ABCB1 3435C>T (rs1045642) in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment. Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration. The relationship between plasma efavirenz concentrations and ABCB1 3435C>T polymorphisms was analyzed. Results: Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age, gender, body weight, CD4 count and plasma HIV-1 RNA, blood biochemical parameters, antiretroviral duration or ABCB1 3435C>T polymorphisms, except for height (OR=0.902, 95% CI: 0.835-0.973) (PT was 0.446. The frequency of the heterozygous mutant ABCB1 3435C/ T was 53.02% (n=79), ABCB1 3435T/T homozygous mutant was 18.12% (n=27) and the wild type ABCB1 3435C/C genotype was 28.86% (n=43). The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L [IQR: (1.46-4.12) mg/L]. The plasma concentration of efavirenz was higher in cases with ABCB1 3435T/T homozygous mutant [2.73 mg/L, IQR: (2.02-4.19) mg/L] and ABCB1 3435C/T heterozygous mutant [2.29 mg/L, IQR: (1.41-4.28) mg/L] genotypes compared to the wild type ABCB1 3435C/C homozygous [2.1 mg/L, IQR: (1.37-3.53) mg/L]. However, there was no statistically significant difference in the efavirenz concentration between the different genotypes (P>0.05). Conclusions: There is no statistical significance for a tendency toward higher plasma efavirenz concentration in the ABCB1 3435T/T and ABCB1 3435C/T genotypes. No parameters of physiological characteristics in this study except for height were found to be predictors of high plasma efavirenz concentration in Thai HIV-1 infected cases.

Effect of ABCB1 3435C>T transporter gene polymorphism on plasma efavirenz concentration in HIV-1 infected Thai adults

Objective: To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1. Methods: A single nucleotide polymorphism of ABCB1 3435C>T (rs1045642) in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment. Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration. The relationship between plasma efavirenz concentrations and ABCB1 3435C>T polymorphisms was analyzed. Results: Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age, gender, body weight, CD4 count and plasma HIV-1 RNA, blood biochemical parameters, antiretroviral duration or ABCB1 3435C>T polymorphisms, except for height (OR=0.902, 95% CI: 0.835-0.973) (PT was 0.446. The frequency of the heterozygous mutant ABCB1 3435C/ T was 53.02% (n=79), ABCB1 3435T/T homozygous mutant was 18.12% (n=27) and the wild type ABCB1 3435C/C genotype was 28.86% (n=43). The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L [IQR: (1.46-4.12) mg/L]. The plasma concentration of efavirenz was higher in cases with ABCB1 3435T/T homozygous mutant [2.73 mg/L, IQR: (2.02-4.19) mg/L] and ABCB1 3435C/T heterozygous mutant [2.29 mg/L, IQR: (1.41-4.28) mg/L] genotypes compared to the wild type ABCB1 3435C/C homozygous [2.1 mg/L, IQR: (1.37-3.53) mg/L]. However, there was no statistically significant difference in the efavirenz concentration between the different genotypes (P>0.05). Conclusions: There is no statistical significance for a tendency toward higher plasma efavirenz concentration in the ABCB1 3435T/T and ABCB1 3435C/T genotypes. No parameters of physiological characteristics in this study except for height were found to be predictors of high plasma efavirenz concentration in Thai HIV-1 infected cases.

Ausencia de asociación entre polimorfismos de los genes ABCB1 c.C3435T y ABCC2 c. -24C>T con epilepsia farmacorresistente en pacientes peruanos / Lack of association between ABCB1 and ABCC2 gene polymorphisms and drug-resistant epilepsy in Peruvian patients

Las variantes de los genes ABCB1 y ABCC2 han sido asociadas a mayor riesgo de epilepsia farmacorresistente pero tal proceso ha sido poco estudiado mediante comparaciones entre poblaciones. En Latinoamérica solo se han realizado 3 estudios. Objetivo: Evaluar la asociación entre las variantes C3435T del gen ABCB1 y -24C>T del gen ABCC2 con epilepsia farmacorresistente en pacientes peruanos atendidos en la Unidad de Epilepsia del Hospital Nacional Edgardo Rebagliati Martins (HNERM). Material y Métodos: Se analizaron muestras sanguíneas de 22 pacientes con epilepsia farmacorresistente y ocho pacientes con epilepsia de respuesta favorable a tratamiento farmacológico, entre Mayo 2016 y Junio 2017. La identificación de la variante C3435T del gen ABCB1 se realizó mediante reacción de cadena de la polimerasa y posterior digestión enzimática; la variante -24C>T del gen ABCC2 se obtuvo por secuenciación. Resultados: Se obtuvo una frecuencia alélica de 0,717 para C en la variante C3435T del gen ABCB1 y 0,967 para C en la variante -24C>T del gen ABCC2. La comparación de las frecuencias alélicas y genotípicas entre pacientes farmacorresistentes y farmacorrespondedores no mostró diferencia significativa, de lo cual se infiere ausencia de asociación entre la epilepsia farmacorresistente y las variantes C3435T del gen ABCB1 y -24C>T del gen ABCC2 (p>0.05). Conclusiones: En una muestra de pacientes peruanos con epilepsia, no se encontró asociación entre epilepsia farmacorresistente y los polimorfismos C3435T del gen ABCB1 y -24C>T del gen ABCC2.

Variants of the genes ABCB1 and ABCC2 have been associated with an increased risk of drug-resistant epilepsy; this phenomenon, however, has been scarcely tested by means of comparisons between populations: In Latin America there have only been 3 studies. Objective: To evaluate the association between the variants C3435T of the gene ABCB1, and --24C> T of the gene ABCC2 with drug-resistant epilepsy in Peruvian patients treated at the Epilepsy Unit of a Peruvian Hospital. Material and Methods: Blood samples from 22 patients with drug-resistant epilepsy and eight patients with pharmaco-responsive epilepsy were analyzed between May 2016 and June 2017. The identification of the C3435T variant of the ABCB1 gene was performed by polymerase chain reaction (PCR) and subsequent enzymatic digestion; the -24C>T variant of the ABCC2 gene was obtained by sequencing. Results: An allelic frequency of 0.717 was obtained for C in the C3435T variant of the gene ABCB1, and 0.967 for C in the-24C> T variant of the gene ABCC2. When genetic and allelic frequencies were compared between drug-resistant and drug-responsive patients no significant difference was observed, from which a lack of association between drug-resistant epilepsy and the C3435T variant of the gene ABCB1 and the -24C> T variant of the gene ABCC2 (p>0.05) was inferred. Conclusions: In a sample of Peruvian patients with epilepsy, no association was found between drug-resistant epilepsy and the C3435T and -24C>T polymorphisms of the genes ABCB1 and ABCC2, respectively.

ABCB1 and BMI1 mRNA expression in patients with chronic myeloid leukemia: impact on imatinib efficacy

BACKGROUND: ATP-binding cassette transporters are important in the mechanism of multidrug resistance. ABCB1 displays a high affinity for imatinib. BMI1 is a polycomb group protein thought to be overexpressed in leukemic cells. METHODS: This study was conducted to investigate the prognostic value of ABCB1 and BMI1 expressions in chronic myeloid leukemia (CML). Expression levels were measured in 81 patients newly diagnosed with CML and 20 healthy controls by real time reverse transcription- PCR. RESULTS: The ABCB1 expression levels did not differ between patients with CML and controls. Low ABCB1 mRNA levels were observed in patients who achieved an optimal response compared to suboptimal and resistant cases (P=0.005). Non-responders showed the highest ABCB1 levels. ABCB1 expression did not affect the progression-free survival (PFS) of patients. BMI1 expression was higher in patients than that in controls (P=0.001). Patients in advanced phases expressed higher levels of BMI1 than those in the chronic phase (P=0.004). High BMI1 expression was associated with a shorter PFS. CONCLUSION: ABCB1 mRNA expression may serve as a predictor of the optimal response to imatinib treatment in patients with CML. BMI1 expression was higher in the accelerated and blastic crisis phases of CML and associated with a shorter PFS.

Relationship between drug resistance andABCB1 gene in pancreatic cancer / 中国肿瘤生物治疗杂志

@#Objective: To investigate the relationship between drug resistance and expression of ABC-binding cassette subfamily B member 1 (ABCB1) as well as its promoter methylation in pancreatic cancer. Methods: Fifteen pairs of pancreatic cancerous tissues and corresponding para-cancerous tissues, which were pathologically verified in Fujian Cancer Hospital from August 2015 to August 2018, were collected for this study; in addition, 3 cases of normal pancreatic tissues and pancreatic cancer cell line SW1990 were also collected. Gemcitabine (GEM)-resistant human pancreatic cancer cell line SW1990/GZ was induced by intermittent concentration gradient multiplication method. The expression level ofABCB1 in SW1990 cells, SW1990/GZ cells, pancreatic cancer tissues and apara-cancerous tissues was detected by qPCR. Methylation of ABCB1 promoter region in SW1990 cells, SW1990/GZ cells and pancreatic cancerous tissues was determined by MSP-PCR. Results: Compared with SW1990 cells, the morphology of SW1990/GZ cells showed more vacuoles, more mitotic images, clumpy growth and increased drug resistance (P<0.05). ABCB1 expression in pancreatic cancer tissues was significantly higher than that in para-cancerous tissues (P<0.01). The expression of ABCB1 in SW1990 and SW1990/GZ cells was significantly higher than that in normal pancreatic tissues (P<0.05 or P<0.01), and the expression of ABCB1 in SW1990/GZ cells was higher than that in SW1990 cells (P<0.05). ABCB1 promoters in SW1990, SW1990/GZ cells and normal pancreatic tissues were hypomethylated. Rate of methylation in pancreatic can cerous tissues and normalpancreatic tissues was 6.7%(1/15) and 0.00%(0/3) respectively,and the difference was statistically insignificant (all P>0.05). Conclusion: Increased ABCB1 expression in pancreatic cancer tissues and cells is associated with drug resistance, but its gene expression does not depend on promoter methylation regulation.

Relationship between ABCB1 Gene Polymorphism and Tacrolimus-related ADR in Renal Transplant Patients during Periopera- tive Period / 中国药房

OBJECTIVE： To investigate the relationship between ATP-binding cassette subfamily B member 1 （ABCB1） polymorphism and tacrolimus-related adverse drug reactions in renal transplant patients during perioperative period. METHODS： Totally 170 patients who underwent renal transplantation from Nov. 2014 to Mar. 2018 in our hospital as well as were tested for their ABCB1 C1236T （rs1128503）， ABCB1 G2677T/A （rs2032582） and ABCB1 C3435T （rs1045642） genotype were selected in this study. χ2 test was used to compare the incidence of tacrolimus-related ADR among patients with different genotypes. The related adverse reactions included digestive tract reaction， pulmonary infection， renal dysfunction， abnormal liver function， elevated blood sugar， elevated blood lipid and decreased white blood cells. Logistic regression model was used to analyze the unit point risk. The main haplotypes of the above genes were analyzed by PHASE software， and their correlation with tacrolimus-induced ADR was analyzed. RESULTS： Among 170 patients， 21 cases （12.3％） of CC type， 78 cases （45.9％） of CT type and 71 cases （41.8％） of TT type were detected by ABCB1 C1236T （rs1128503）. ABCB1 G2677T/A （rs2032582） test showed that 25 cases （14.7％） were GG type， 95 cases （55.9％） were GA+GT type and 50 cases （29.4％） were AA+AT+TT type. ABCB1 C3435T （rs1045642） test showed that 57 cases （33.5％） were CC type， 82 cases （48.2％） were CT type and 31 cases （18.3％） were TT type. There was no significant difference in the incidence of digestive tract reaction， pulmonary infection， renal dysfunction， elevated blood sugar， elevated blood lipid and decreased white blood cells among patients with different ABCB1 genotypes （P＞0.05）. However， there was significant difference in the incidence of abnormal liver function between ABCB1 C1236T （rs1128503） and ABCB1 C3435T （rs1045642） genotypes （P＜0.05）. There was no significant difference in the incidence of abnormal liver function among ABCB1 G2677T/A （rs2032582） genotypes （P＝0.069）， but P was lower than 0.1. Logistic regression analysis showed that ABCB1 C1236T （rs1128503） CC genotype [OR＝4.959， 95％CI （1.700， 14.468）， P＝0.003]， ABCB1 G2677T/A （rs2032582） GG genotype [OR＝3.500， 95％CI （1.164， 10.524）， P＝0.026] and ABCB1 C3435T （rs1045642） CC genotype [OR＝3.033， 95％CI （1.012， 9.095）， P＝0.048] were risk factors for tacrolimus-related abnormal liver function. ABCB1 CGC haplotype was the main haplotype. There was significant difference in the incidence of abnormal liver function caused by tacrolimus between ABCB1 CGC haplotype and non-ABCB1 CGC haplotype （P＝0.002）， and it was also a risk factor for tacrolimus-related liver dysfunction [OR＝3.173， 95％CI（1.512， 6.656）， P＝0.002]. CONCLUSIONS： The abnormal liver function of ABCB1 CGC haplotype kidney transplantation patients is more likely to occur when tacrolimus is administered during the perioperative period.

Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression

Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.

The epigallocatechin gallate derivative Y reverses drug resistance mediated by the ABCB1 transporter both and

Previously, we reported that Y, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y in reversing drug resistance both and by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

Relationship between ABCB1 gene polymorphism and metoprolol′s clinical efficacy / 实用医学杂志

Objective To investigate the correlation between ABCB1 gene C3435T polymorphism and clinical efficacy of metoprolol,provided a theoretical basis for the precise treatment of hypertension. Methods A total of 120 patients with essential hypertension level 1 or level 2 and a resting heart rate of 80 beats were enrolled in the hospital from October 2016 to October 2017 at the First Affiliated Hospital of Jiamusi University.According to ABCB1 C3435T genotype,all patients were divided into CC group(n=40),CT group(n=57),TT group(n=16)and given oral metoprolol sustained-release tablets 47.5 mg/d.The metoprolol plasma concentration were mea-sured after one week.All subjects followed up to record the mean blood pressure and mean heart rate before and after treatment after four weeks,were compared the changes in blood pressure and heart rate before and after treatment and analyzed the clinical efficacy.Results The standard plasma concentration in group TT[(39.23±6.42)μg/L vs. (45.68±7.43)μg/L],the difference of mean systolic blood pressure before and after treatment in TT group[(18.8± 11.13)mmHg vs.(44±9.05)mmHg],the difference of mean systolic blood pressure before and after treatment in CT group[(26.91±9.33)mmHg vs.(44±9.05)mmHg],the difference of mean diastolic blood pressure before and after treatment in TT group[(11.6 ± 6.59)mmHg vs.(23.75 ± 7.47)mmHg],the difference of mean diastolic blood pressure before and after treatment in CT group[(14.73 ± 6.02)mmHg vs.(23.75 ± 7.47)mmHg]were significantly lower than those in CC group(all P<0.01).After treatment,the antihypertensive effect of CC group was significantly better than TT group(χ2= 6.132,P = 0.013). There was no significant difference in the rate of heart rate among three groups(χ2= 0.484,P = 0.785). There was no significant difference in the mean heart rate among the three groups before and after treatment(F = 1.278,P = 0.293). Conclusions The differences among three groups of genotype patients showed that the different genotypes of ABCB1 gene C3435T were related to the clinical efficacy of metoprolol,which provide a new idea and theoretical basis for the precise treatment of hypertension.

Helioscopianoids A-Q, bioactive jatrophane diterpenoid esters from

The EtOH extracts of the whole plants of afforded 17 new jatrophane diterpenoid esters, helioscopianoids A-Q (-), along with eight known compounds (-). Their structures were elucidated by extensive spectroscopic methods and Mo(OAc)-induced ECD analysis, and the structures of compounds , , and were confirmed by X-ray crystallography. Compounds - were evaluated for inhibitory effects on P-glycoprotein (P-gp) in an adriamycin (ADM)-resistant human breast adenocarcinoma cell line (MCF-7/ADR) and neuroprotective effects against serum deprivation-induced and rotenone-induced PC12 cell damage. Compounds and increased the accumulation of ADM in MCF-7/ADR cells by approximately 3-fold at a concentration of 20 μmol/L. Compound could attenuate rotenone-induced PC12 cell damage, and compounds , , and showed neuroprotective activities against serum deprivation-induced PC12 cell damage.