Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L.; Sarkaria, Jann N.; Prehn, Jochen H.M.

doi:10.3389/fnins.2015.00218

Cited by 100 publications

(88 citation statements)

References 26 publications

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“…For instance, enforced expression of MRP1 enhanced adriamycin (ADR) chemoresistance of prostate cancer cells [12]. MRP1 inhibition improved chemosensitivity of glioblastoma multiforme cells to vincristine (VCR) and etoposide [13]. Moreover, MRP1 has been demonstrated to be correlated with the reduction of survival rate and worse prognosis in breast cancer [14,15].…”

Section: Introductionmentioning

confidence: 99%

Linc00518 Contributes to Multidrug Resistance Through Regulating the MiR-199a/MRP1 Axis in Breast Cancer

Chang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long non-coding RNAs (LncRNAs) have been validated to be pivotal mediators in multidrug resistance (MDR) of various cancers. This study aims to explore the roles and molecular mechanisms of linc00518 implicated in chemoresistance in breast cancer. Methods: Expressions of linc00518, miR-199a and MRP1 were evaluated by RT-qPCR or western blot. IC 50 values of adriamycin (ADR), vincristine (VCR) and paclitaxel (PTX) were determined by XTT assays and cell apoptosis was assessed by flow cytometry. Luciferase reporter and RIP assays were employed to detect the interaction of linc00518, miR-199a and MRP-1. Results: linc00518 expression increased nearly 2 fold and MRP1 level elevated about 2.5 fold in breast cancer tissues as compared to that in adjacent normal tissues. Also, almost 2 fold upregulation of linc00518 and MRP-1 expressions was observed in MCF-7 cells than in MCF-10A cells. Additionally, linc00518 level was almost 2.5 fold higher and MRP1 level was about 2 fold increased in ADR-resistant MCF-7 cells (MCF-7/ADR) than in parental cell line MCF-7. Linc00518 knockdown enhanced chemosensitivity to ADR, VCR and PTX, and boosted ADR-, VCR-and PTX-induced apoptosis in MCF-7/ADR cells. miR-199a inhibitor conferred chemoresistance to ADR, VCR and PTX in MCF-7/ADR cells, and suppressing miR-199a reversed multi-drug susceptibility induced by linc00518 knockdown. Furthermore, linc00518 could act as a molecular sponge of miR-199a to repress MRP1 expression. MRP1 depletion increased the sensitivity of MCF-7/ADR cells to ADR, VCR and PTX, and this effect was attenuated following miR-199a inhibition or linc00518 overexpression. Also, linc00518 silencing increased ADRmediated anti-tumor effect in vivo. Conclusions: linc00518 downregulation reduced MDR by regulating miR-199a/MRP1 axis in breast cancer.

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Section: Introductionmentioning

confidence: 99%

Linc00518 Contributes to Multidrug Resistance Through Regulating the MiR-199a/MRP1 Axis in Breast Cancer

Chang

Zhou

et al. 2018

Cell Physiol Biochem

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“…RNAi with non-enzymatic targets was also observed to be valuable in sensitizing cells to TMZ: In a previous study, it was noted that silencing the voltage-gated potassium channel Eag1 makes glioblastoma cells more vulnerable to TMZ (71). The same effect occurred for drug resistance proteins, heat-shock proteins 90, 27 and 72, and other targets involved in cell signaling (72)(73)(74)(75)(76)(77).…”

Section: Discussionmentioning

confidence: 73%

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

Resende

Titze‐de‐Almeida

2018

Oncol Lett

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Abstract. Astrocytic tumors, including astrocytomas and glioblastomas, are the most common type of primary brain tumors. Treatment for glioblastomas includes radiotherapy, chemotherapy with temozolomide (TMZ) and surgical ablation. Despite certain therapeutic advances, the survival time of patients is no longer than 12-14 months. Cancer cells overexpress the neuronal isoform of nitric oxide synthase (nNOS). In the present study, it was examined whether the nNOS enzyme serves a role in the damage of astrocytoma (U251MG and U138MG) and glioblastoma (U87MG) cells caused by TMZ. First, TMZ (250 µM) triggered an increase in oxidative stress at 2, 48 and 72 h in the U87MG, U251MG and U138MG cell lines, as revealed by 2',7'-dichlorofluorescin-diacetate assay. The drug also reduced cell viability, as measured by MTT assay. U87MG cells presented a more linear decline in cell viability at time-points 2, 48 and 72 h, compared with the U251MG and U138MG cell lines. The peak of oxidative stress occurred at 48 h. To examine the role of NOS enzymes in the cell damage caused by TMZ, N(ω)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) were used. L-NAME increased the cell damage caused by TMZ while reducing the oxidative stress at 48 h. The preferential nNOS inhibitor 7-NI also improved the TMZ effects. It caused a 12.8% decrease in the viability of TMZ-injured cells. Indeed, 7-NI was more effective than L-NAME in restraining the increase in oxidative stress triggered by TMZ. Silencing nNOS with a synthetic small interfering (si)RNA (siRNAnNOShum_4400) increased by 20% the effects of 250 µM of TMZ on cell viability (P<0.05). Hoechst 33342 nuclear staining confirmed that nNOS knock-down enhanced TMZ injury. In conclusion, our data reveal that nNOS enzymes serve a role in the damage produced by TMZ on astrocytoma and glioblastoma cells. RNA interference with nNOS merits further studies in animal models to disclose its potential use in brain tumor anticancer therapy.

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“…The molecular mechanism underlying VCR resistance is complex and involves a number of genes, including insulin-like growth factor-binding protein 7 and multidrug resistance protein 1, in addition to long non-coding RNA (20)(21)(22). In the present study, a VCR-resistant cell line (HCT-8/V) was established to explore the mechanism of drug resistance in colon cancer cells to VCR by gradually increasing the drug concentration during cell culture.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 expression serves a role in vincristine resistance in colon cancer cells

Zhang

2017

Oncology Letters

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Abstract. The present study aimed to investigate the association between breast cancer susceptibility gene 1 (BRCA1) expression and drug resistance in colon cancer, with the specific aim of elucidating the underlying molecular mechanisms of vincristine (VCR) resistance in tumor cells. The HCT-8 human colon cancer cell line was used to establish the VCR-resistant HCT-8/V line by gradually increasing the concentration of VCR during cell culture. The relative mRNA and protein expression levels of BRCA1 in these colon cancer cell lines was assessed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting, respectively. Resistance to VCR was established in the HCT-8/V colon cancer cells, and RT-qPCR and western blot analysis revealed the expression of BRCA1 to be significantly higher in the VCR-resistant cells compared with their drug-sensitive counterparts (P<0.05). The decreased BRCA1 expression in these VCR-resistant cells may be associated with the drug resistance frequently observed in colon cancer. IntroductionColon cancer is one of the most common malignant tumors of the digestive system. With economic development and changes in lifestyle, the incidence of colon cancer is increasing, endangering human life and health (1). Chemotherapy is an important treatment strategy for colon cancer (2); however, it is a long process involving drug combinations and the administration of large doses of drugs. Tumor drug resistance has become increasingly frequent and is a problem for the treatment of colon cancer and other malignant tumors (3). Notably, 90% of cancer mortalities are associated with tumor drug resistance (4), therefore the underlying molecular mechanisms regulating the development of drug resistance are a key focus of malignant tumor research. Mechanisms of drug resistance in tumors include the modification of drug targets, repair of damaged cells, and the activation or inhibition of cell death signaling pathways. These processes can result from gene mutations, deletions or amplifications, in addition to epigenetic changes that occur via abnormal DNA methylation or the post-transcriptional regulation of microRNAs (miRNAs) (5-7).Vincristine (VCR), the most frequently used chemotherapy drug in the clinical treatment of colon cancer, is a cell cycle-specific drug that binds to tubulin, thereby inhibiting the assembly of microtubule structures and arresting mitosis in metaphase (8). The tumor suppressor breast cancer susceptibility gene 1 (BRCA1) confers increased susceptibility to breast and ovarian cancers, and mutations in the BRCA1 gene are present in ≤50% of inherited breast cancers (9,10). In women <50 years old, the risk of colorectal cancer is increased in carriers of BRCA1 mutations (11).In the current study, the expression of BRCA1 was verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting, to investigate the role of BRCA1 in modulating VCR resistance. The findings reported here demonstrate potential...

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Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

Cited by 100 publications

References 26 publications

Linc00518 Contributes to Multidrug Resistance Through Regulating the MiR-199a/MRP1 Axis in Breast Cancer

Linc00518 Contributes to Multidrug Resistance Through Regulating the MiR-199a/MRP1 Axis in Breast Cancer

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

BRCA1 expression serves a role in vincristine resistance in colon cancer cells

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