Drug Efflux by Breast Cancer Resistance Protein Is a Mechanism of Resistance to the Benzimidazole Insulin-Like Growth Factor Receptor/Insulin Receptor Inhibitor, BMS-536924

Hou, Xiaonan; Huang, Fei; Carboni, Joan M.; Flatten, Karen S.; Asmann, Yan W.; Eyck, Cynthia Ten; Nakanishi, Takeo; Tibodeau, Jennifer D.; Ross, Douglas D.; Gottardis, Marco M.; Erlichman, Charles; Kaufmann, Scott H.; Haluska, Paul

doi:10.1158/1535-7163.mct-10-0438

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…Cancer cells are more dependent on the glycolytic pathway for ATP generation, compared with normal cells, and they eventually acquire drug resistance, typically due to the aberrant expression of drug-expelling ABC transporters (12). The ATP-dependence of drug transporters for activity (40,41) suggests that glycolysis inhibition may increase the concentration of chemotherapeutic agents in cancer cells (42,43). The most widely studied transporters, including MRP1, BCRP and P-gp, are able to transport a variety of structurally-unassociated chemotherapeutic compounds from cancer cells, thereby inducing MDR (44).…”

Section: Discussionmentioning

confidence: 99%

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Liu¹,

Sun²

2017

Oncology Letters

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Abstract. Shikonin (SHK) is a natural naphthoquinone pigment isolated from Lithospermum erythrorhizon, that has been reported to suppress the growth of a number of cancer cell types. Adriamycin (AD) is typically used as an effective anticancer agent; however, it has the propensity to induce drug resistance. The aim of the present study was to investigate the effects of SHK alone and in combination with AD on lung adenocarcinoma cells and the underlying molecular mechanisms of their effects. Colony formation, MTT and propidium iodide staining assays demonstrated that the co-treatment of A549 cells with SHK and AD significantly decreased cell viability and potently induced apoptosis. The mitochondrial membrane potential was assessed using 5,5', 6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide staining and fluorescence microscopy. Cells co-treated with SHK and AD exhibited marked mitochondrial membrane damage. In addition, co-treatment with SHK and AD significantly reduced ATP levels in A549 cells compared with the control. Western blot analysis revealed that SHK enhanced the antitumor effects of AD by inhibiting the expression of ATP-binding cassette transporters. These results suggest that the inhibition of glycolysis could be an effective approach for lung cancer treatment. Therefore, SHK has the potential to be used as an anticancer agent in the treatment of lung adenocarcinoma, and thus warrants further investigation and development.

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Section: Discussionmentioning

confidence: 99%

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Liu¹,

Sun²

2017

Oncology Letters

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“…Moreover, several studies have demonstrated a functional role of miRNA mediated transfer of exosomes to recipient cells (Valadi et al, 2007; Kosaka et al, 2010; Pegtel et al, 2010; Yang et al, 2011; Montecalvo et al, 2012). Tumor-suppressive miRNA’s have been shown to be functional when transferred by exosomes in a ceramide dependent manner in prostate cancer cell lines (Kosaka et al, 2010).…”

Section: Role Of Exosomal Shuttle Rna In Neurodegenerative Diseasementioning

confidence: 99%

“…While immature and mature dendritic cells can package and release miRNA in exosomes dependent upon their activation state, with released exosomes fusing with recipient cell plasma membranes transferring functional miRNA into the cytosol (Montecalvo et al, 2012). Macrophages can also regulate the invasiveness of breast cancer through exosome-mediated delivery of miRNA into cells promoting metastasis (Yang et al, 2011). Exosomes can also functionally deliver ncRNA, retroviral RNA repeats and tRNA sequences which are subsequently incorporated into RNA-silencing pathways (Gibbings et al, 2009; Lee et al, 2009; Haussecker et al, 2010).…”

Section: Role Of Exosomal Shuttle Rna In Neurodegenerative Diseasementioning

confidence: 99%

Exosomes: Vehicles for the Transfer of Toxic Proteins Associated with Neurodegenerative Diseases?

et al. 2012

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Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell–cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer’s disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson’s disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.

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“…+ T cells and human MCF7 cells, we selected genes with high and medium levels (5664 and 7895, respectively) of expression based on RNAseq (Koch et al 2011) and microarray data (Heintzman et al 2009;Hou et al 2011), respectively. We filtered out all genes for which there was another annotated gene in either strand within a region of 2.3 Kb flanking the poly(A) site according to the UCSC KnownGene genes annotations for hg19 and mm9 genome versions (Rhead et al 2010).…”

Section: /Cd8mentioning

confidence: 99%

Dynamic transitions in RNA polymerase II density profiles during transcription termination

Grosso¹,

Almeida²,

Braga³

et al. 2012

Genome Res.

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Eukaryotic protein-coding genes are transcribed by RNA polymerase II (RNAPII) through a cycle composed of three main phases: initiation, elongation, and termination. Recent studies using chromatin immunoprecipitation coupled to high-throughput sequencing suggest that the density of RNAPII molecules is higher at the 39-end relative to the gene body. Here we show that this view is biased due to averaging density profiles for ''metagene'' analysis. Indeed, the majority of genes exhibit little, if any, detectable accumulation of polymerases during transcription termination. Compared with genes with no enrichment, genes that accumulate RNAPII at the 39-end are shorter, more frequently contain the canonical polyadenylation [poly(A)] signal AATAAA and G-rich motifs in the downstream sequence element, and have higher levels of expression. In 1% to 4% of actively transcribing genes, the RNAPII enriched at the 39-end is phosphorylated on Ser5, and we provide evidence suggesting that these genes have their promoter and terminator regions juxtaposed. We also found a striking correlation between RNAPII accumulation and nucleosome organization, suggesting that the presence of nucleosomes after the poly(A) site induces pausing of polymerases, leading to their accumulation. Yet we further observe that nucleosome occupancy at the 39-end of genes is dynamic and correlates with RNAPII density. Taken together, our results provide novel insight to transcription termination, a fundamental process that remains one of the least understood stages of the transcription cycle.[Supplemental material is available for this article.]Eukaryotic protein-coding genes are transcribed by a molecular engine powered by RNA polymerase II (RNAPII). Transcription is a repetitive, cyclic process composed of three main phases: initiation, elongation, and termination (Fuda et al. 2009). The transcription cycle starts with RNAPII gaining access to the promoter, unwinding DNA and initiating RNA synthesis. RNAPII must then get a stable grip on both the template DNA and the growing RNA chain and proceed elongating through the entire body of the gene. Finally, the RNA is released and RNAPII can reinitiate to start a new round of transcription. In mammals, termination by RNAPII can occur anywhere from a few base pairs to several kilobases downstream from the annotated 39-end of the gene, which corresponds to the polyadenylation [poly ( the other results from a ''torpedo'' effect on RNAPII induced by rapid exonuclease degradation of the 59-uncapped RNA produced after cleavage at the poly(A) site.Transcription termination plays a vital role in cells because it controls gene expression and ensures genomic partitioning (Kuehner et al. 2011). However, termination remains one of the least understood stages of the transcription cycle. Recent studies using chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-seq) revealed higher average polymerase density downstream from the polyadenylation [poly(A)] site compared with the transcribed region (Rahl e...

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Drug Efflux by Breast Cancer Resistance Protein Is a Mechanism of Resistance to the Benzimidazole Insulin-Like Growth Factor Receptor/Insulin Receptor Inhibitor, BMS-536924

Abstract: Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer.

Cited by 19 publications

References 29 publications

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Exosomes: Vehicles for the Transfer of Toxic Proteins Associated with Neurodegenerative Diseases?

Dynamic transitions in RNA polymerase II density profiles during transcription termination

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