Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes

Tseng, Yuan Yun; Huang, Yin Chen; Yang, Tao; Yang, Shun Tai; Liu, Shou Cheng; Chang, Tzu Min; Kau, Yi Chuan; Liu, Shih‐Jung

doi:10.1038/srep30630

Cited by 18 publications

(13 citation statements)

References 42 publications

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“…However, patients subjected to these treatments do not exceed, on average, ~15 months of survival [ 5 ]. At the same time, the incorporation of new strategies such as anti-proliferative, anti-angiogenic, and immunological therapies have not achieved a great improvement in survival rates [ 5 , 7 , 8 , 9 ], so the search for new therapeutic alternatives for GBM has become highly relevant in recent years [ 5 , 10 ]. Studies from ours and other laboratories have found that the main factor that leads to the failure of chemotherapy in GBM is the expression and activity of ATP binding cassette (ABC) transporters [ 3 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells

Torres

Arriagada

Erices

et al. 2018

IJMS

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Poor response to current treatments for glioblastoma has been attributed to the presence of glioblastoma stem-like cells (GSCs). GSCs are able to expel antitumor drugs to the extracellular medium using the multidrug resistance-associated protein 1 (MRP1) transporter. Tacrolimus (FK506) has been identified as an MRP1 regulator in differentiated glioblastoma (GBM) cells (non-GSCs); however, the effect of FK506 on GSCs is currently unknown. The objective of the following research is to evaluate the effect of FK506 on the MRP1-related chemo-resistant phenotype of GSCs. For this, U87MG and C6 glioma cell lines were used to generate non-GSCs and GSCs. mRNA and MRP1-positive cells were evaluated by RT-qPCR and flow cytometry, respectively. A Carboxyfluorescein Diacetate (CFDA)-retention assay was performed to evaluate the MRP1 activity. Apoptosis and MTT assays were employed to evaluate the cytotoxic effects of FK506 plus Vincristine (MRP1 substrate). GSC-derived subcutaneous tumors were generated to evaluate the in vivo effect of FK506/Vincristine treatment. No differences in transcript levels and positive cells for MRP1 were observed in FK506-treated cells. Lesser cell viability, increased apoptosis, and CFDA-retention in the FK506/Vincristine-treated cells were observed. In vivo, the FK506/Vincristine treatment decreased the tumor size as well as ki67, Glial Fibrillary Acidic Protein (GFAP), and nestin expression. We conclude that FK506 confers a chemo-sensitive phenotype to MRP1-drug substrate in GSCs.

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Section: Introductionmentioning

confidence: 99%

FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells

Torres

Arriagada

Erices

et al. 2018

IJMS

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“…Theoretically, higher drug concentrations possess more efficient therapeutic effects and prevent tumour resistance. In vitro studies have shown that BCNU-resistant human glioma cells are effectively killed at a BCNU concentration of 250 lM (53.75 lg/mL) [51]. The HSNMs developed in this study released concentrations of BCNU higher than 200 lg/mL for more than 14 weeks.…”

Section: Discussionmentioning

confidence: 93%

Biodegradable hybrid-structured nanofibrous membrane supported chemoprotective gene therapy enhances chemotherapy tolerance and efficacy in malignant glioma rats

Liu

Yang

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Chemotherapy is ineffective for treating malignant glioma (MG) because of the low therapeutic levels of pharmaceuticals in tumour tissues and the well-known tumour resistance. The resistance to alkylators is modulated by the DNA repair protein O-alkylguanine-DNA alkyltransferase (AGT). O-benzylguanine (O-BG) can irreversibly inactivate AGT by competing with O-methylguanine and has been confirmed to increase the therapeutic activity of alkylators. We developed hybrid-structured poly[(d,l)-lactide-co-glycolide] nanofibrous membranes (HSNMs) that enable the sequential and sustained release of O-BG and two alkylators (carmustine and temozolomide [TMZ]). HSNMs were surgically instilled into the cerebral cavity of pathogen-free rats and F98 glioma-bearing rats. The release behaviours of loaded drugs were quantified by using high-performance liquid chromatography. The treatment results were compared with the rats treated with intraperitoneal injection of O-BG combined with surgical implantation of carmustine wafer and oral TMZ. The HSNMs revealed a sequential drug release behaviour with the elution of high drug concentrations of O-BG in the early phase, followed by high levels of two alkylators. All drug concentrations remained high for over 14 weeks. Tumour growth was slower and the mean survival time was significantly prolonged in the HSNM-treated group. Biodegradable HSNMs can enhance therapeutic efficacy and prevent toxic systemic effects.

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“…Despite major developments in therapeutic interventions, GB is one of the most lethal and invasive malignancies of the central nervous system and is the leading cause of overall cancer-associated mortality. Patients with GB exhibit poor prognosis [ 26 ] and the current therapy mostly fails because these patients develop multidrug resistance and do not respond to the treatment [ 27 , 28 , 29 ]. Studies have shown that lncRNAs are widely accepted and play a crucial role in the development, progression, and metastasis of cancer as well as in drug resistance of GB.…”

Section: Discussionmentioning

confidence: 99%

Targeting BC200/miR218-5p Signaling Axis for Overcoming Temozolomide Resistance and Suppressing Glioma Stemness

Lin

Shih

et al. 2020

Cells

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Background: Glioblastoma (GB) is one of the most common (~30%) and lethal cancers of the central nervous system. Although new therapies are emerging, chemoresistance to treatment is one of the major challenges in cancer treatment. Brain cytoplasmic 200 (BC200) RNA, also known as BCYRN1, is a long noncoding RNA (lncRNA) that has recently emerged as one of the crucial members of the lncRNA family. BC200 atypical expression is observed in many human cancers. BC200 expression is higher in invasive cancers than in benign tumors. However, the clinical significance of BC200 and its effect on GB multiforme is still unexplored and remains unclear. Methods: BC200 expression in GB patients and cell lines were investigated through RT-qPCR, immunoblotting, and immunohistochemistry analysis. The biological importance of BC200 was investigated in vitro and in vivo through knockdown and overexpression. Bioinformatic analysis was performed to determine miRNAs associated with BC200 RNA. Results: Our findings revealed that in GB patients, BC200 RNA expression was higher in blood and tumor tissues than in normal tissues. BC200 RNA expression have a statistically significant difference between the IDH1 and P53 status. Moreover, the BC200 RNA expression was higher than both p53, a prognostic marker of glioma, and Ki-67, a reliable indicator of tumor cell proliferation activity. Overexpression and silencing of BC200 RNA both in vitro and in vivo significantly modulated the proliferation, self-renewal, pluripotency, and temozolomide (TMZ) chemo-resistance of GB cells. It was found that the expressions of BC200 were up-regulated and that of miR-218-5p were down-regulated in GB tissues and cells. miR-218-5p inhibited the expression of BC200. Conclusions: This study is the first to show that the molecular mechanism of BC200 promotes GB oncogenicity and TMZ resistance through miR-218-5p expression modulation. Thus, the noncoding RNA BC200/miR-218-5p signaling circuit is a potential clinical biomarker or therapeutic target for GB.

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Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes

Cited by 18 publications

References 42 publications

FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells

FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells

Biodegradable hybrid-structured nanofibrous membrane supported chemoprotective gene therapy enhances chemotherapy tolerance and efficacy in malignant glioma rats

Targeting BC200/miR218-5p Signaling Axis for Overcoming Temozolomide Resistance and Suppressing Glioma Stemness

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