Characterization of carfilzomib-resistant non-small cell lung cancer cell lines

Hanke, Neale T.; Imler, Elliot; Marron, Marilyn T.; Seligmann, Bruce; Garland, Linda; Baker, Amanda F.

doi:10.1007/s00432-018-2662-0

Cited by 15 publications

(10 citation statements)

References 31 publications

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“…In the case of newer platforms such as TempO-Seq targeted RNA sequencing, there has not been an evaluation of the performance of several normalization methods. Recent publications using the TempO-Seq platform used DESeq2 or CPM for normalization (Grimm et al, 2016;House et al, 2017;Yeakley et al, 2017;Batai et al, 2018;Bushel et al, 2018;Hanke et al, 2018;Limonciel et al, 2018;Chappell et al, 2019;Ramaiahgari et al, 2019;Simon et al, 2019). In this study, we compared seven normalization methods using simulated data from human HepaRG control cells to determine which methods maintained genes at seven assigned FC levels ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, by nature of the technology, it lacks 3 end bias. Recently, several studies utilized the TempO-Seq platform for whole transcriptome profiling, primarily for toxicogenomics (Grimm et al, 2016;House et al, 2017;Yeakley et al, 2017;Bushel et al, 2018;Limonciel et al, 2018;Chappell et al, 2019;Ramaiahgari et al, 2019;Simon et al, 2019), but also carcinogenomics (Batai et al, 2018;Hanke et al, 2018), and to profile formalin-fixed paraffin-embedded (FFPE) tissue (Trejo et al, 2019). However, there has not been a comprehensive comparison of normalization methods applied to TempO-Seq data.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Normalization Methods for Analysis of TempO-Seq Targeted RNA Sequencing Data

et al. 2020

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Analysis of bulk RNA sequencing (RNA-Seq) data is a valuable tool to understand transcription at the genome scale. Targeted sequencing of RNA has emerged as a practical means of assessing the majority of the transcriptomic space with less reliance on large resources for consumables and bioinformatics. TempO-Seq is a templated, multiplexed RNA-Seq platform that interrogates a panel of sentinel genes representative of genome-wide transcription. Nuances of the technology require proper preprocessing of the data. Various methods have been proposed and compared for normalizing bulk RNA-Seq data, but there has been little to no investigation of how the methods perform on TempO-Seq data. We simulated count data into two groups (treated vs. untreated) at seven-fold change (FC) levels (including no change) using control samples from human HepaRG cells run on TempO-Seq and normalized the data using seven normalization methods. Upper Quartile (UQ) performed the best with regard to maintaining FC levels as detected by a limma contrast between treated vs. untreated groups. For all FC levels, specificity of the UQ normalization was greater than 0.84 and sensitivity greater than 0.90 except for the no change and +1.5 levels. Furthermore, K-means clustering of the simulated genes normalized by UQ agreed the most with the FC assignments [adjusted Rand index (ARI) = 0.67]. Despite having an assumption of the majority of genes being unchanged, the DESeq2 scaling factors normalization method performed reasonably well as did simple normalization procedures counts per million (CPM) and total counts (TCs). These results suggest that for two class comparisons of TempO-Seq data, UQ, CPM, TC, or DESeq2 normalization should provide reasonably reliable results at absolute FC levels ≥2.0. These findings will help guide researchers to normalize TempO-Seq gene expression data for more reliable results.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of Normalization Methods for Analysis of TempO-Seq Targeted RNA Sequencing Data

et al. 2020

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“…12a was coupled with right-hand Boc-deprotected epoxyketone intermediate 4c using the general procedure for the amide coupling reaction to prepare 25 as a white solid (31%). 1 [4,7,10]triazacyclohexadecine-3-carboxamide (26). Macrocyclic carboxylic acid intermediate 15a was prepared from 14a using the general procedure for synthesis of macrocyclic carboxylic acid.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Recently, we reported that iP-targeting linear peptide epoxyketones (e.g., DB-310, Figure b) have a previously unrecognized effect of alleviating cognitive deficits in mouse models of AD in a manner independent of Aβ and tau aggregation. , We also showed that the iP inhibitors lower the levels of serum interleukin-1α (IL-1α) and protect the retinal pigment epithelium (RPE) layer from the structural destruction caused by Aβ-triggered inflammation in Tg2576 mice, potentially representing a new class of AD drugs that aim at a previously untapped pathway in AD drug discovery efforts. Despite promising efficacy, however, these linear peptide epoxyketones’ clinical prospect seems limited at this time due to issues commonly associated with linear peptides, such as poor brain penetration and metabolic instability (mainly attributable to transporter-mediated efflux and enzymatic metabolism). ,− Yet, the peptide epoxyketone family (“short peptides with C-terminal α′,β′-epoxyketone warhead”) provides an attractive drug development platform for related diseases due to pharmacological advantages conferred by their proven target specificity for the proteasomes and long-term safety in the clinic …”

Section: Introductionmentioning

confidence: 99%

Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer’s Disease

et al. 2021

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Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC 50 : 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.

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“…Generally, P-gp mediates the resistance of cytotoxic and targeted chemotherapeutics by transporting them out of cancer cells without chemical modification [4]. Previous studies have found that P-gp is overexpressed in resistant breast cancer, lung cancer and colon cancer cells [5,6,7], as well as in patients with neuroblastoma, acute myeloid leukemia, acute lymphoblastic leukemia [8,9,10,11] and many other cancers [12], indicating that it is an important target, the inhibitor of which is emerging as one promising approach to overcome MDR [13,14]. However, the development of such small molecules has been unsuccessful, mainly due to unexpected severe adverse effects and/or low efficacy in improving the therapeutic outcomes as measured in clinical trials [15,16].…”

Section: Introductionmentioning

confidence: 99%

Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells

Cui

Cai

Wang

et al. 2019

IJMS

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P-glycoprotein (P-gp), which is encoded by the ATP-binding cassette (ABC) transporter subfamily B member 1 (ABCB1) gene, is one of the most pivotal ABC transporters that transport its substrates across the cell membrane. Its overexpression is one of the confirmed causes of multidrug resistance (MDR), which results in the failure of cancer treatment. Here, we report that checkpoint kinase (Chk) 1 inhibitor MK-8776, a drug candidate in clinical trial, can restore the sensitivity of chemotherapeutics that are substrates of P-gp in KB-C2, SW620/Ad300 cells and human embryonic kidney (HEK)293/ABCB1 cells that overexpress P-gp. MK-8776 remarkably enhanced the cellular [3H]-paclitaxel accumulation and suppressed the efflux function of P-gp without reducing its expression and affecting its cellular localization in cancer cells. Furthermore, MK-8776 (0–40 μM) stimulated the activity of ATPase in P-gp, which was 4.1-fold greater than the control. In addition, MK-8776 formed a cation–π bond and π–π interaction with key residues of the substrate-binding site in P-gp, as indicated by computer-aided molecular docking study. Our study indicated that MK-8776 may significantly enhance the sensitivity of chemotherapeutics that are substrates of P-gp, providing important information for its application in the reversal of MDR.

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Characterization of carfilzomib-resistant non-small cell lung cancer cell lines

Abstract: Upregulation of Pgp appears to be an important, but not the only, mechanism of CFZ resistance in NSCLC cell lines.

Cited by 15 publications

References 31 publications

Comparison of Normalization Methods for Analysis of TempO-Seq Targeted RNA Sequencing Data

Comparison of Normalization Methods for Analysis of TempO-Seq Targeted RNA Sequencing Data

Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer’s Disease

Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells

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