Triapine-mediated ABCB1 induction via PKC induces widespread therapy unresponsiveness but is not underlying acquired triapine resistance

Miklos, Walter; Pelivan, Karla; Kowol, Christian R.; Pirker, Christine; Dornetshuber-Fleiss, Rita; Spitzwieser, Melanie; Englinger, Bernhard; Schoonhoven, Sushilla van; Cichna‐Markl, Margit; Koellensperger, Gunda; Keppler, Bernhard K.; Berger, Walter; Heffeter, Petra

doi:10.1016/j.canlet.2015.02.049

Cited by 24 publications

(55 citation statements)

References 50 publications

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“…resistance or collateral sensitivity), we characterized the toxicity of the compounds in a panel of drug sensitive and MDR cell lines. In agreement with literature data, we find that Triapine is subject to MDR [20,21,48], while the isatin-β-TSCs around 1a show MDR-selective activity [15,21,40,43,44].…”

Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 92%

“…Similarly, introduction of a phenyl substituent to the N4 position has been shown to increase the toxicity of dipyridylketone TSCs to a comparable extent as terminal dimethylation [23,47]. In contrast to Dp44mT and NSC73306, the toxicity of the terminally unsubstituted NNS thiosemicarbazone Triapine is attenuated by P-gp [20,21,48].…”

Section: Design and Synthesis Of A Focused Chelator Librarymentioning

confidence: 99%

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Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Pape

Tóth

Füredi

et al. 2016

European Journal of Medicinal Chemistry

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Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 92%

Section: Design and Synthesis Of A Focused Chelator Librarymentioning

confidence: 99%

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Pape

Tóth

Füredi

et al. 2016

European Journal of Medicinal Chemistry

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“…However, we found no ABCB1 gene dose alteration in DMS114/NIN cells by indirect aCGH (Figure 7A). Decreased methylation of seven CpG dinucleotides in the ABCB1 promoter downstream the transcription start site (from +524 to +587) was previously found to be associated with enhanced gene expression [21]. However, DNA methylation of all these CpG dinucleotides was below the pyrosequencing limit of quantification in both the parental DMS114 cells and the resistant subline (data not shown).…”

Section: Resultsmentioning

confidence: 74%

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

et al. 2016

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Genomically amplified fibroblast growth factor receptor 1 (FGFR1) is an oncogenic driver in defined lung cancer subgroups and predicts sensibility against FGFR1 inhibitors in this patient cohort. The FGFR inhibitor nintedanib has recently been approved for treatment of lung adenocarcinoma and is currently evaluated for small cell lung cancer (SCLC). However, tumor recurrence due to development of nintedanib resistance might occur. Hence, we aimed at characterizing the molecular mechanisms underlying acquired nintedanib resistance in FGFR1-driven lung cancer. Chronic nintedanib exposure of the FGFR1-driven SCLC cell line DMS114 (DMS114/NIN) but not of two NSCLC cell lines induced massive overexpression of the multidrug-resistance transporter ABCB1. Indeed, we proved nintedanib to be both substrate and modulator of ABCB1-mediated efflux. Importantly, the oncogenic FGFR1 signaling axis remained active in DMS114/NIN cells while bioinformatic analyses suggested hyperactivation of the endothelin-A receptor (ETAR) signaling axis. Indeed, ETAR inhibition resensitized DMS114/NIN cells against nintedanib by downregulation of ABCB1 expression. PKC and downstream NFκB were identified as major downstream players in ETAR-mediated ABCB1 hyperactivation. Summarizing, ABCB1 needs to be considered as a factor underlying nintedanib resistance. Combination approaches with ETAR antagonists or switching to non-ABCB1 substrate FGFR inhibitors represent innovative strategies to manage nintedanib resistance in lung cancer.

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“…The functional relevance of the DNA methylation status of the seven CpGs in the ABCB1 promoter has been discovered recently. A significant difference was found in the DNA methylation status of these CpGs between parental SW480 cells and SW480/tria, a triapine-resistant subline overexpressing ABCB1 [47]. In addition, Reed et al reported significant hypomethylation of this region in drug-resistant sublines of MCF-7 compared to the parental breast cancer cell line [28].…”

Section: Discussionmentioning

confidence: 99%

Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

et al. 2016

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Overexpression of ABCB1, ABCC1 and ABCG2 in tumor tissues is considered a major cause of limited efficacy of anticancer drugs. Gene expression of ABC transporters is regulated by multiple mechanisms, including changes in the DNA methylation status. Most of the studies published so far only report promoter methylation levels for either ABCB1 or ABCG2, and data on the methylation status for ABCC1 are scarce. Thus, we determined the promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in 19 human cancer cell lines. In order to contribute to the elucidation of the role of DNA methylation changes in acquisition of a multidrug resistant (MDR) phenotype, we also analyzed the promoter methylation patterns in drug-resistant sublines of the cancer cell lines GLC-4, SW1573, KB-3-1 and HL-60. In addition, we investigated if aberrant promoter methylation levels of ABCB1, ABCC1 and ABCG2 occur in tumor and tumor-surrounding tissues from breast cancer patients.Our data indicates that hypomethylation of the ABCC1 promoter is not cancer type-specific but occurs in cancer cell lines of different origins. Promoter methylation was found to be an important mechanism in gene regulation of ABCB1 in parental cancer cell lines and their drug-resistant sublines. Overexpression of ABCC1 in MDR cell models turned out to be mediated by gene amplification, not by changes in the promoter methylation status of ABCC1. In contrast to the promoters of ABCC1 and ABCG2, the promoter of ABCB1 was significantly higher methylated in tumor tissues than in tumor-adjacent and tumor-distant tissues from breast cancer patients.

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Triapine-mediated ABCB1 induction via PKC induces widespread therapy unresponsiveness but is not underlying acquired triapine resistance

Cited by 24 publications

References 50 publications

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

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