ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide

Malmström, Per; Łysiak, M; Åkesson, Lisa; Falk, Ingrid Jakobsen; Mudaisi, Munila; Milos, Peter; Hallbeck, Martin; Fomichov, Victoria; Broholm, Helle; Grunnet, Kirsten; Poulsen, Hans Skovgaard; Bratthäll, Charlotte; Strandéus, Michael; Papagiannopoulou, Angeliki; Stenmark-Askmalm, Marie; Gréen, Henrik; Söderkvist, Peter

doi:10.1038/s41397-019-0107-z

Cited by 13 publications

(11 citation statements)

References 22 publications

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“…The second cohort was a population-based cohort of 179 patients from South-East Sweden with IDH wt GBM and known MGMT methylation status, analyzed by pyrosequencing ( Table 1 ). Patients were recruited from 2004 and onwards and followed until death or until last follow-up (1 December 2020) [ 20 ]. Histological diagnosis of IDH wt GBM was obtained by biopsy or tumor resection, and all patients received postoperative RT concomitant with TMZ.…”

Section: Methodsmentioning

confidence: 99%

Sex Disparities in MGMT Promoter Methylation and Survival in Glioblastoma: Further Evidence from Clinical Cohorts

Smits

Łysiak

Magnusson

et al. 2021

JCM

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Introduction: Recent studies suggest an overrepresentation of MGMT promoter methylated tumors in females with IDHwt glioblastoma (GBM) compared to males, with a subsequent better response to alkylating treatment. Methods: To reveal sex-bound associations that may have gone unnoticed in the original analysis, we re-analyzed two previously published clinical cohorts. One was the multicenter Nordic trial of elderly patients with GBM, randomizing patients into three different treatment arms, including 203 cases with known MGMT promoter methylation status. The other was a population-based study of 179 patients with IDHwt GBM, receiving concomittant radiotherapy and chemotherapy with temozolomide. Cohorts were stratified by sex to test the hypothesis that female sex in combination with MGMT promoter methylation constitutes a subgroup with more favorable outcome. Results: There was a significantly larger proportion of MGMT promoter methylation and better outcome for female patients with MGMT promoter methylated tumors. Results were confirmed in 257 TCGA-derived IDHwt GBM with known sex and MGMT status. Conclusions: These results confirm that patient sex in combination with MGMT promoter methylation is a key determinant in GBM to be considered prior to treatment decisions. Our study also illustrates the need for stratification to identify such sex-bound associations.

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Section: Methodsmentioning

confidence: 99%

Sex Disparities in MGMT Promoter Methylation and Survival in Glioblastoma: Further Evidence from Clinical Cohorts

Smits

Łysiak

Magnusson

et al. 2021

JCM

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“…Exploring compounds to antagonize MDR is of importance to improve the efficiency of chemotherapy [1]. ABCB1 (also known as MDR1, encoding ABCB1 gene) is a transmembrane glycoprotein that participates in the process of drug metabolism [2,3]. In a physiological state, ABCB1 can protect our bodies' microenvironments by extruding various endogenous ligands and exogenous drugs.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Wang

Yang

et al. 2020

IJMS

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The overexpressing ABCB1 transporter is one of the key factors leading to multidrug resistance (MDR). Thus, many ABCB1 inhibitors have been found to be able to overcome ABCB1-mediated MDR. However, some inhibitors also work as a substrate of ABCB1, which indicates that in order to achieve an effective reversal dosage, a higher concentration is needed to overcome the pumped function of ABCB1, which may concurrently increase the toxicity. WYE-354 is an effective and specific mTOR (mammalian target of rapamycin) inhibitor, which recently has been reported to reverse ABCB1-mediated MDR. In the current study, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability and reversal effect of WYE-354 in parental and drug-resistant cells. Drug accumulation was performed to examine the effect of WYE-354 on the cellular accumulation of chemotherapeutic drugs. The ATPase (adenosine triphosphatase) activity of the ABCB1 transporter in the presence or absence of WYE-354 was conducted in order to determine the impact of WYE-354 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate the protein molecules related to MDR. In addition, the interaction between the WYE-354 and ABCB1 transporter was investigated via in silico analysis. We demonstrated that WYE-354 is a substrate of ABCB1, that the overexpression of the ABCB1 transporter decreases the efficacy of WYE-354, and that the resistant WYE-354 can be reversed by an ABCB1 inhibitor at a pharmacological achievable concentration. Furthermore, WYE-354 increased the intracellular accumulation of paclitaxel in the ABCB1-mediated MDR cell line, without affecting the corresponding parental cell line, which indicated that WYE-354 could compete with other chemotherapeutic drugs for the ABCB1 transporter substrate binding site. In addition, WYE-354 received a high score in the docking analysis, indicating a strong interaction between WYE-354 and the ABCB1 transporter. The results of the ATPase analysis showed that WYE-354 could stimulate ABCB1 ATPase activity. Treatment with WYE-354 did not affect the protein expression or subcellular localization of the ABCB1. This study provides evidence that WYE-354 is a substrate of the ABCB1 transporter, implicating that WYE-354 should be avoided for use in ABCB1-mediated MDR cancer.

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“…Important genes involved in lipid metabolism in these GO terms include ABCB1, ABCC1, FABP4. These genes are involved in the lipid metabolism of GBM by in uencing cell growth, proliferation, angiogenesis and invasion [52,53]. GO analysis con rmed that XFZYD treats GBM by regulating of oxidative stress and lipid metabolism.…”

Section: Go Enrichment Analysis Of Ccg Targetsmentioning

confidence: 96%

System Pharmacology-Based Strategy to Investigate Core Component Group and Molecular Mechanisms of Xuefu Zhuyu Decoction in the Treatment of Gbm

Wang

Yang

et al. 2021

Preprint

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BackgroundXuefu Zhuyu Decoction (XFZYD) is a well-known Traditional Chinese Medicine (TCM) formula that has many pharmacological effects, including enhancing immune function, improving hemorheology and regulating blood vessels bidirectionally. Modern pharmacological and clinical studies showed that XFZYD could ameliorate curative effect of glioblastoma (GBM). The aim of this study was to interpret core components and the hidden molecular mechanisms of XFZYD on GBM. MethodsHere, a novel network pharmacology strategy, which combined pharmacological data, next generation sequencing data, pharmacokinetic parameters and a novel node importance calculation method was designed to decipher the potential therapeutic mechanism of XFZYD on GBM. The partial components in core component group (CCG) were evaluated by in vitro expriments. We identified 117 chemical components analysis through ADME screening, then component-target network and GBM related genes were integrated as the component-target-pathogenic gene (C-T-P) network. ResultsThe results show that the enriched pathways of targets in the key functional network could cover 77.92% of the enriched pathways of pathogenic genes. A novel cumulative contribution rate (CCR) calculation model was designed and captured CCG with 21 components. The statistics results indicate that 15 enriched pathways of the targets of CCG were overlap with pathogenic genes enriched pathways. Finally, some core components in CCG were validated by in vitro experiments. ConclusionThe results show that our proposed stategy for decoding CCG and infering the underlying mechanism with good reliability and accuracy. The validation results indicate that the CCG play a therapeutic role on GBM by targeting to PI3K-Akt signaling pathway and Toll-like receptor signaling pathway. Our strategy provides methodological reference for the optimization and secondary development of TCM formula.

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ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide

Cited by 13 publications

References 22 publications

Sex Disparities in MGMT Promoter Methylation and Survival in Glioblastoma: Further Evidence from Clinical Cohorts

Sex Disparities in MGMT Promoter Methylation and Survival in Glioblastoma: Further Evidence from Clinical Cohorts

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

System Pharmacology-Based Strategy to Investigate Core Component Group and Molecular Mechanisms of Xuefu Zhuyu Decoction in the Treatment of Gbm

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