Retinoic-acid-resistant neuroblastoma cell lines show alteredMYC regulation and high sensitivity to fenretinide

Reynolds, C. Patrick; Wang, Y.; Melton, L. Joseph; Einhorn, P.A.; Slamon, DJ; Maurer, Barry J.

doi:10.1002/1096-911x(20001201)35:6<597::aid-mpo23>3.0.co;2-b

Cited by 73 publications

(64 citation statements)

References 16 publications

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“…Unlike retinoic acid, fenretinide is able to induce apoptosis in a range of neuroblastoma cell lines, including some which are resistant to retinoic acid. 4 This makes fenretinide a potentially powerful agent for the treatment of neuroblastoma.…”

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confidence: 99%

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

et al. 2005

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confidence: 99%

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

et al. 2005

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“…Treatment with 13cisRA for high-risk neuroblastoma takes place after high dose myeloablative therapy and radiotherapy but the most appropriate way to utilise fenretinide remains unclear. In vitro data showing that neuroblastoma cells selected for 13cisRA resistance are sensitive to fenretinide suggest that fenretinide may be useful for MRD remaining after 13cisRA treatment (5). However, the mechanisms of action of 13cisRA in vivo are unknown and in vitro selection may not be an appropriate model of treatment failure since it has not been demonstrated that patients who relapse after retinoid therapy do so because of inherent retinoid resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, prolonged disease stabilisation was induced in some neuroblastoma patients participating in a phase I trial when treated during partial remission (3). These encouraging clinical data, together with the observation that neuroblastoma cells shown to be resistant to 13cisRA are sensitive to fenretinide (5), have led to the incorporation of fenretinide in the treatment of MRD in a phase II trial. However, it is known that retinoic acid (RA) treatment can increase resistance to apoptotic agents (6)(7)(8), and whilst combining fenretinide with 13cisRA represents a promising clinical approach, there are important questions over the potential for interactions between these drugs which have yet to be addressed.…”

Section: Introductionmentioning

confidence: 99%

“…A previous study describing the potential importance of Bcl-2 and Bcl-xL up-regulation during neuronal differentiation and subsequent resistance to apoptosis is therefore of particular relevance (7). Conversely, neuroblastoma cells treated intermittently with a high concentration of all-trans RA (ATRA) in vitro to select for cells resistant to differentiation were hypersensitive to fenretinide (5). These data indicate that cells sensitive to RA (able to differentiate in response to RA) may be resistant to subsequent treatment with agents that induce apoptosis, while cells unable to respond to RA would remain sensitive.…”

Section: Introductionmentioning

confidence: 99%

“…As neuroblastoma is notoriously heterogeneous, cells exhibiting these properties may exist as subpopulations within a tumour and influence response to therapy. Analysis of fenretinide cytotoxicity in a panel of neuroblastoma cell lines which were established from patients at various phases of therapy, including myeloablative therapy and 13cisRA treatment, revealed a range of sensitivities to fenretinide, with resistance more apparent post-treatment (5). Therefore, 13cisRA therapy may influence response to subsequent treatment with fenretinide in subsets of patients.…”

Section: Introductionmentioning

confidence: 99%

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The impact of retinoic acid treatment on the sensitivity of neuroblastoma cells to fenretinide

Armstrong

Martin²,

Illingworth³

et al. 2011

Oncol Rep

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Abstract. Despite the successful introduction of 13-cis retinoic acid (13cisRA) therapy for the treatment of neuroblastoma, approximately 50% patients do not respond or experience relapse. A retinoid analogue, fenretinide [N-(4-hydroxyphenyl) retinamide; 4-HPR] can induce apoptosis in neuroblastoma cell lines and could have clinical use after therapy with 13cisRA. However, there are important questions concerning potential retinoid drug interactions which need to be addressed. The aim of this study was to investigate the influence of retinoic acid pre-treatment on fenretinide-induced apoptosis and fenretinide metabolism in neuroblastoma cell lines. Apoptosis was measured by flow cytometry of propidium iodide-stained neuroblastoma cells and a live-cell imaging assay. Intracellular fenretinide metabolism was determined by HPLC analysis. Pre-treatment of neuroblastoma cell lines with retinoic acid (RA) resulted in a significant decrease in the apoptotic response to fenretinide in three of the four lines tested. Comparison between responsive and non-responsive cell lines suggested that RA sensitivity was required to promote fenretinide resistance, and that this was mediated by up-regulation of Bcl-2 and the inhibition of pro-apoptotic fenretinide signalling pathways. Induction of the oxidative metabolism of fenretinide after RA pre-treatment did not significantly impact on intracellular parent drug levels and is unlikely to explain the decreased apoptotic response observed. The interaction between RA and fenretinide could have important implications for the scheduling of fenretinide in therapeutic protocols for neuroblastoma.

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P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models

López-Barcons

Maurer

Kang

et al. 2017

Intl Journal of Cancer

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We previously reported that concurrent ketoconazole, an oral anti-fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4-HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4-HPR cytotoxic dose-response in four neuroblastoma (NB) cell lines in vitro and on 4-HPR activity against two cell line-derived, subcutaneous NB xenografts (CDX) and three patient-derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay. Xenografted animals were treated with 4-HPR/LXS (240 mg/kg/day) + ketoconazole (38 mg/kg/day) in divided oral doses in cycles of five continuous days a week. In one model, intratumoral levels of 4-HPR and metabolites were assessed by HPLC assay, and in two models intratumoral apoptosis was assessed by TUNEL assay, on Day 5 of the first cycle. Antitumor activity was assessed by Kaplan-Meier event-free survival (EFS). The in vitro cytotoxicity of 4-HPR was not affected by ketoconazole (p ≥ 0.06). Ketoconazole increased intratumoral levels of 4-HPR (p = 0.02), of the active 4-oxo-4-HPR metabolite (p = 0.04), and intratumoral apoptosis (p ≤ 0.0006), compared to 4-HPR/LXS-alone. Concurrent ketoconazole increased EFS in both CDX models compared to 4-HPR/LXS-alone (p ≤ 0.008). 4-HPR + ketoconazole also increased EFS in PDX models compared to controls (p ≤ 0.03). Thus, concurrent ketoconazole decreased 4-HPR metabolism with resultant increases of plasma and intratumoral drug levels and antitumor effects in neuroblastoma murine xenografts. These results support the clinical testing of concurrent ketoconazole and oral fenretinide in neuroblastoma.

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Retinoic-acid-resistant neuroblastoma cell lines show alteredMYC regulation and high sensitivity to fenretinide

Abstract: Thus, RA-resistant NB cell lines can be sensitive (and in some cases collaterally hypersensitive) to 4-HPR.

Cited by 73 publications

References 16 publications

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

The impact of retinoic acid treatment on the sensitivity of neuroblastoma cells to fenretinide

P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models

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