Showing papers on "Multidrug Resistance Protein 1 published in 2017"
TL;DR: The data suggest that the knockdown of HOTAIR may play a crucial role in improving acquired resistance to imatinib in CML K562-R cells via PI3K/Akt pathway.
Abstract: Objectives: Imatinib, a breakpoint cluster region-Abelson murine leukemia tyrosine kinase inhibitor, has revolutionized the treatment of chronic myelogenous leukemia (CML). However, the development of multidrug resistance (MDR) limits the clinical application of imatinib. In this study, we aimed to investigate the mechanisms of long noncoding RNA (lncRNA) HOTAIR in CML resistance to imatinib.Methods: Thirty-four CML patients were divided into multidrug resistance protein 1 (MRP1)-low and MRP1-high groups according to the median expression. Real-time PCR (qPCR) was used to detect the expression of lncRNA HOTAIR in CML patients, and MTT assay and flow cytometry assay were employed to detect the biological function of silencing lncRNA HOTAIR on the cell survival rate and apoptotic rate. An imatinib-resistant human CML cell line K562 (K562-R) was established, and western blot was used to detect the impact of lncRNA HOTAIR on the activation of PI3K/Akt signaling pathway.Results: Our results showed that...
68 citations
TL;DR: The C60+Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo, overcoming drug resistance likely by the potential of the C60 fullerene to interact with P-gp, MRp-1, and MRP-2 molecules.
Abstract: We formulated and analyzed a novel nanoformulation of the anticancer drug cisplatin (Cis) with C60 fullerene (C60+Cis complex) and showed its higher toxicity toward tumor cell lines in vitro when compared to Cis alone. The highest toxicity of the complex was observed in HL-60/adr and HL-60/vinc chemotherapy-resistant human leukemia cell sublines (resistant to Adriamycin and Vinculin, respectively). We discovered that the action of the C60+Cis complex is associated with overcoming the drug resistance of the tumor cell lines through observing an increased number of apoptotic cells in the Annexin V/PI assay. Moreover, in vivo assays with Lewis lung carcinoma (LLC) C57BL/6J male mice showed that the C60+Cis complex increases tumor growth inhibition, when compared to Cis or C60 fullerenes alone. Simultaneously, we conducted a molecular docking study and performed an Ames test. Molecular docking specifies the capability of a C60 fullerene to form van der Waals interactions with potential binding sites on P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP-1), and multidrug resistance protein 2 (MRP-2) molecules. The observed phenomenon revealed a possible mechanism to bypass tumor cell drug resistance by the C60+Cis complex. Additionally, the results of the Ames test show that the formation of such a complex diminishes the Cis mutagenic activity and may reduce the probability of secondary neoplasm formation. In conclusion, the C60+Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo, overcoming drug resistance likely by the potential of the C60 fullerene to interact with P-gp, MRP-1, and MRP-2 molecules. Thus, the C60+Cis complex might be a potential novel chemotherapy modification.
60 citations
TL;DR: It is revealed that EVs from HL60/AR can interact with HL60 cells and transfer at least partially, their chemo-resistance, and two microRNAs were highlighted for their high differential expression in EVs related to sensitive or Chemo-resistant cells: miR-19b and miR20a.
53 citations
TL;DR: It is suggested that targeting peroxisome proliferator–activated receptor γ might serve as an effective approach for circumventing multidrug resistance in chemotherapy of cancerous patients.
Abstract: Multidrug resistance in tumor cells is still a big challenge in cancer treatment. Therefore, identification ofsafe and effective multidrug resistance-reversing compounds with minimal side effects is an important approach in cancer treatment. Here, we investigated the role and potential mechanisms of peroxisome proliferator-activated receptor γ in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effect of doxorubicin on cell viability following treatment with balaglitazone, a peroxisome proliferator-activated receptor γ agonist, was evaluated using trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Rhodamine123 assay was used to determine the activity of two common drug efflux membrane transporters P-glycoprotein and multidrug resistance protein-1. P-glycoprotein, multidrug resistance protein-1, and phosphatase and tensin homolog deleted on chromosome 10 messenger RNA/protein expression levels were measured by quantitative reverse transcription polymerase chain reaction and western blot analyses. Annexin V/fluorescein isothiocyanate assay was also employed to investigate apoptosis. We showed that balaglitazone considerably enhanced the cytotoxicity of doxorubicin. Balaglitazone also significantly downregulated P-glycoprotein expression and activity in K562/DOX cells and reduced multidrug resistance through elevation of intracellular doxorubicin in cells. Furthermore, upon balaglitazone treatment, phosphatase and tensin homolog deleted on chromosome 10 expression could be restored in K562/DOX cells in a peroxisome proliferator-activated receptor γ-dependent manner. We concluded that peroxisome proliferator-activated receptor γ agonist, balaglitazone, could reverse multidrug resistance by inducing phosphatase and tensin homolog deleted on chromosome 10 and peroxisome proliferator-activated receptor/ phosphatase and tensin homolog deleted on chromosome 10 signaling pathway. These findings suggest that targeting peroxisome proliferator-activated receptor γ might serve as an effective approach for circumventing multidrug resistance in chemotherapy of cancerous patients.
42 citations
TL;DR: The effectiveness of the high content imaging‐based high‐throughput assay for profiling compound interaction with MRP1 was demonstrated and it was demonstrated that the identified compounds exert differential and selective response on the uptake of estradiol glucuronide, an endogenous MRP substrate.
39 citations
TL;DR: Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of β- catenin accumulation and nuclear translocation.
Abstract: Multidrug resistance is a great obstacle in successful chemotherapy of colorectal cancer. However, the molecular mechanism underlying multidrug resistance is not fully understood. Dishevelled, a pivot in Wnt signaling, has been linked to cancer progression, while its role in chemoresistance remains unclear. Here, we found that Dishevelled1-3 was over-expressed in multidrug-resistant colorectal cancer cells (HCT-8/VCR) compared to their parental cells. Silencing Dishevelled1-3 resensitized HCT-8/VCR cells to multiple drugs including vincristine, 5-fluorouracil and oxaliplatin. Moreover, Dishevelled1-3 increased the protein levels of multidrug resistance protein 1 (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), Survivin and Bcl-2 which are correlated with multidrug resistance. shβ-catenin abolished Dishevelled-mediated these protein expressions. Unexpectedly, none of Dishevelled1-3 controlled β-catenin accumulation and nuclear translocation. Furthermore, the nuclear translocations of Dishevelled1-3 were promoted in HCT-8/VCR cells compared to HCT-8. Dishevelled1-3 bound to β-catenin in nucleus, and promoted nuclear complex formation and transcription activity of β-catenin/TCF. Taken together, Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of β-catenin accumulation and nuclear translocation. Silencing Dishevelled1-3 resensitized multidrug-resistant colorectal cancer cells, providing a novel therapeutic target for successful chemotherapy of colorectal cancer.
25 citations
TL;DR: Examination of primary renal transporters in rats revealed that kidney transporter expression is affected by ontogeny and aging, which may impact drug and toxicant disposition in children and the elderly.
Abstract: Kidney transporters are involved in the secretion and reabsorption of endogenous and exogenous molecules. Numerous factors may influence their expression and affect drug disposition, efficacy and toxicity. The present study aimed to examine the development‑ and age‑associated variations in primary renal transporters in rats, including 6 uptake transporters: Organic anion transporter (OAT) 1 and 3, organic cation transporter (OCT) 1, 2 and 3 and organic anion‑transporting polypeptide (OATP) 4C1, and 6 efflux transporters: Multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance‑associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2‑K. Kidneys from male Sprague Dawley rats during development (‑2, 1, 7, 14 and 21 days), maturation (28, 35 and 60 days) and aging (180, 540 and 850 days) were collected and total RNA was extracted, purified and subjected to reverse transcription‑quantitative polymerase chain reaction analysis. Total proteins were extracted for western blot analysis. OAT1 and 3, OCT1, BCRP, MRP2 and 4 and MATE2‑K expression levels were low in fetal kidneys, increased gradually following birth and markedly increased on maturation and adulthood. High levels were maintained until 850 days. OCT2, OATP4C1, Mdr1b and MATE1 expression levels were low in fetal kidneys, increased gradually following birth, and increased markedly on weaning, maturation and adulthood; however, levels were decreased on aging. OCT3 mRNA expression levels were low in fetal and newborn kidneys, and had two peaks at 35 and 850 days. The selected OAT1 and 3 and MDR1 protein expression levels revealed a similar expression pattern. Thus, kidney transporter expression is affected by ontogeny and aging, which may impact drug and toxicant disposition in children and the elderly.
25 citations
TL;DR: This review targets MRP1 which becomes, when overexpressed, the so called "Achilles' heel" of multidrug resistant cancer cells, and discusses the link between the prominent role of glutathione translocation and related redox balance of the cell and the CS induced by certain types of compounds.
Abstract: Cancer cells are permanently being selected for survival and proliferation. During this process, tumor cells often co-opt basic physiological mechanisms to protect themselves from toxic chemotherapy. One of these mechanisms is the overexpression of ATP-binding cassette (ABC) drug efflux pumps leading to multidrug resistance (MDR) of cancer cells through an increase of drug efflux. In the past 20 years, many efforts were done to circumvent MDR through the inhibition of ABC transporters. A number of inhibitors of these transporters were found but are rarely specific or rationally developed. Beside this approach, a new therapeutic strategy towards eradicating drug resistant tumor cells has recently emerged from the observation that cancer cells expressing a high level of these pumps show an unexpected hypersensitivity, called collateral sensitivity (CS) to a selected subset of chemical compounds. In this review, we target the multidrug resistance protein 1 (MRP1) and after a non-exhaustively highlighting of some of the most exemplary inhibitors of MRP1 and modulators of its expression, we focus on CS agents specifically targeting MRP1 which becomes, when overexpressed, the so called "Achilles' heel" of multidrug resistant cancer cells. We discuss the link between the prominent role of glutathione translocation and related redox balance of the cell and the CS induced by certain types of compounds. The latter are discussed according to their chemical class, and perspectives in their development for successful eradication of resistant cancer are proposed.
22 citations
TL;DR: The transporter protein expression at the inner BRB was most highly correlated with that at the BBB, followed by outer BRB and BCSFB (R2 = 0.7988), and these findings may be helpful for understanding differential barrier function.
Abstract: The purpose of this study was to determine absolute protein expression levels of transporters at the porcine inner blood–retinal barrier (BRB) and to compare the transporter protein expression quantitatively among the inner BRB, outer BRB, blood–brain barrier (BBB), and blood–cerebrospinal fluid barrier (BCSFB). Crude membrane fractions of isolated retinal capillaries (inner BRB) and isolated retinal pigment epithelium (RPE, outer BRB) were prepared from porcine eyeballs, while plasma membrane fractions were prepared from isolated porcine brain capillaries (BBB) and isolated choroid plexus (BCSFB). Protein expression levels of 32 molecules, including 16 ATP-binding-cassette (ABC) transporters and 13 solute-carrier (SLC) transporters, were measured using a quantitative targeted absolute proteomic technique. At the inner BRB, five molecules were detected: breast cancer resistance protein (BCRP, ABCG2; 22.8 fmol/μg protein), multidrug resistance protein 1 (MDR1, ABCB1; 8.70 fmol/μg protein), monocarboxylate ...
21 citations
TL;DR: The results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinOBlastoma with chemotherapy.
Abstract: Aim To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. Methods Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC) were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin) were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. Results Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp) was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1) expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp) was observed in the drug resistant Y79 cells as well as in PCNC. Conclusion Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy.
19 citations
TL;DR: The results of the present study suggest that miR-93-5p serves a role in the development of MDR through downregulating CDKN1A gene expression in CRC through upregulated expression in HCT-8/VCR cells.
Abstract: Multidrug resistance (MDR) impedes successful chemotherapy in colorectal carcinoma (CRC) and emerging evidence suggests that microRNAs (miRs) are involved in the development of MDR. In the present study, the role of miR-93-5p in the modulation of drug resistance in CRC was investigated using HCT-8 and MDR HCT-8/vincristine (VCR) cell lines. The results demonstrated upregulated expression of miR-93-5p and MDR protein 1 (MDR1) in HCT-8/VCR cells, compared with the parental HCT-8 cells. Furthermore, cyclin-dependent kinase inhibitor 1A (CDKN1A) was identified as a potential target of miR-93-5p using miR target analysis tools, including PicTar, TargetScan and miRanda. In addition, inhibition of miR-93-5p expression in HCT-8/VCR cells markedly downregulated MDR1 gene expression, upregulated CDKN1A gene expression and induced cell cycle arrest in G1. Conversely, the overexpression of miR-93-5p in HCT-8/VCR cells upregulated MDR1 gene expression, downregulated CDKN1A gene expression and promoted G1/S transition. Furthermore, the in vitro drug sensitivity assay performed suggested that downregulation of miR-93-5p enhanced the sensitivity of HCT-8/VCR cells to VCR, while the upregulation of miR-93-5p decreased the sensitivity of HCT-8 cells to VCR. In conclusion, the results of the present study suggest that miR-93-5p serves a role in the development of MDR through downregulating CDKN1A gene expression in CRC.
TL;DR: The attenuated expression of BCRP, LRP, and MDR1 along with the breakdown of the inner BRB is found, which may be linked to the pathogenesis of early DR.
Abstract: Aim To investigate the altering expression profiles of efflux transporters such as breast cancer-resistance protein (BCRP), lung resistance protein (LRP), and multidrug resistance protein 1 (MDR1) at the inner blood-retinal barrier (BRB) during the development of early diabetic retinopathy (DR) and/or aging in mice. Methods Relative mRNA and protein expression profiles of these three efflux transporters in the retina during the development of early DR and/or aging in mice were examined. The differing expression profiles of Zonula occludens 1 (ZO-1) and vascular endothelial growth factor-A (VEGFA) in the retina as well as the perfusion characterization of fluorescein isothiocyanate (FITC)-dextran and Evans blue were examined to evaluate the integrity of the inner BRB. Results There were significant alterations in these three efflux transporters' expression profiles in the mRNA and protein levels of the retina during the development of diabetes mellitus and/or aging. The development of early DR was confirmed by the expression profiles of ZO-1 and VEGFA in the retina as well as the compromised integrity of the inner BRB. Conclusion The expression profiles of some efflux transporters such as BCRP, LRP, and MDR1 in mice retina during diabetic and/or aging conditions are tested, and the attenuated expression of BCRP, LRP, and MDR1 along with the breakdown of the inner BRB is found, which may be linked to the pathogenesis of early DR.
TL;DR: LIMK1 serves a key role in the MDR of osteosarcoma and functions through MDR1, and the results demonstrated that the level of MDR 1/P-gp was positively correlated with thelevel of LIMK1.
Abstract: Multidrug resistance (MDR) is a major challenge for the management of the majority of cancers. The precise molecular mechanisms of MDR remain elusive. In a previous study, a multidrug resistant osteosarcoma model [MG63/vincristine (VCR)] was established by intermittent exposure of MG63 cells to gradually increasing concentrations of VCR. These cells exhibited cross-resistance to multiple structurally and mechanistically unrelated chemotherapeutic agents. The development of MDR was associated with increased expression of LIM kinase 1 (LIMK1). Compared with that in normal human fetal osteoblasts (hFOB) 1.19, the messenger RNA and protein expression of LIMK1 was significantly elevated both in MG63 and U2OS osteosarcoma cells. To observe the expression pattern of LIMK1 in osteosarcoma, immunohistochemical analyses were performed on specimens derived from 6 patients. The results indicated that LIMK1 was expressed to a greater extent in the tumor parenchyma than in the mesenchyme. The role of LIMK1 in MDR was confirmed by transfecting plasmids coding LIMK1-small interfering RNA (siRNA), wild-type-LIMK1 or empty vector into MG63/VCR cells, and measuring the expression of LIMK1 and multidrug resistance protein 1 (MDR1), also known as P-gycoprotein (P-gp). The results demonstrated that the level of MDR1/P-gp was positively correlated with the level of LIMK1. This correlation was also shown with the doxorubicin efflux assay and by measuring apoptosis. Specifically, after 6 h of incubation with VCR, 25.6% of the cells transfected with the LIMK1-siRNA plasmid were apoptotic compared with 6.2% in the empty vector group and 1.3% in the group of cells transfected with the wild-type-LIMK1 plasmid. Thus, it was concluded that LIMK1 serves a key role in the MDR of osteosarcoma and functions through MDR1.