Combined RARα- and RXR-specific ligands overcome N-myc-associated retinoid resistance in neuroblastoma cells

Nguyen, Tuan Nghia; Hocker, Jayne E.; Thomas, Wayne; Smith, Stewart A.; Norris, Murray D.; Haber, Michelle; Cheung, Belamy B.; Marshall, Glenn M.

doi:10.1016/s0006-291x(03)00177-3

Cited by 22 publications

(23 citation statements)

References 32 publications

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“…However, CaR expression was not induced in the MYCN-amplified SK-N-BE(2)-C cell line. Whether MYCN-associated retinoid resistance 27 may account for this difference remains to be elucidated. Second, CaR was expressed in 50% of ganglioneuroblastomas and ganglioneuromas, but PTHrP levels higher than the median value were detected in almost 100% of these tumors.…”

Section: Discussionmentioning

confidence: 99%

The calcium‐sensing receptor and parathyroid hormone‐related protein are expressed in differentiated, favorable neuroblastic tumors

Torres

Beleta

Díaz

et al. 2009

Cancer

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Objective Lubricin, also referred to as superficial zone protein and PRG4, is a synovial glycoprotein that supplies a friction‐resistant, antiadhesive coating to the surfaces of articular cartilage, thereby protecting against arthritis‐associated tissue wear and degradation. This study was undertaken to generate and characterize a novel recombinant lubricin protein construct, LUB:1, and to evaluate its therapeutic efficacy following intraarticular delivery in a rat model of osteoarthritis (OA). Methods Binding and localization of LUB:1 to cartilage surfaces was assessed by immunohistochemistry. The cartilage‐lubricating properties of LUB:1 were determined using a custom friction testing apparatus. A cell‐binding assay was performed to quantify the ability of LUB:1 to prevent cell adhesion. Efficacy studies were conducted in a rat meniscal tear model of OA. One week after the surgical induction of OA, LUB:1 or phosphate buffered saline vehicle was administered by intraarticular injection for 4 weeks, with dosing intervals of either once per week or 3 times per week. OA pathology scores were determined by histologic analysis. Results LUB:1 was shown to bind effectively to cartilage surfaces, and facilitated both cartilage boundary lubrication and inhibition of synovial cell adhesion. Treatment of rat knee joints with LUB:1 resulted in significant disease‐modifying, chondroprotective effects during the progression of OA, by markedly reducing cartilage degeneration and structural damage. Conclusion Our findings demonstrate the potential use of recombinant lubricin molecules in novel biotherapeutic approaches to the treatment of OA and associated cartilage abnormalities.

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Section: Discussionmentioning

confidence: 99%

The calcium‐sensing receptor and parathyroid hormone‐related protein are expressed in differentiated, favorable neuroblastic tumors

Torres

Beleta

Díaz

et al. 2009

Cancer

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“…SH-SY5Y cell line is nonamplified, and the BE(2)-C cell line is amplified, for the oncogene MYCN, an important determinant of the RA response in vitro and patient prognosis in vivo (Bordow et al, 1998;Nguyen et al, 2003).…”

Section: Microarray Data and Validation Of A Subset Of Differentiallymentioning

confidence: 99%

The retinoid anticancer signal: mechanisms of target gene regulation

et al. 2005

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Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARb2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARb2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARb2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARb2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellularsignal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARb2, DUSP6, and RGS16.

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“…An interaction between retinoid receptors and other nuclear proteins may be determinants of retinoid responses in NB cells (35). Furthermore, recently, a correlation was reported between N-myc gene amplification and resistance to an all-trans retinoic acid effect in NB cells (36). In our model, which amplifies the N-myc gene, 13-cis RA failed to induce differentiation and inhibition of tumor growth at clinically relevant doses.…”

Section: Discussionmentioning

confidence: 53%

In Vivo Treatment with CPT-11 Leads to Differentiation of Neuroblastoma Xenografts and Topoisomerase I Alterations

Santos¹,

Calvet²,

Terrier-Lacombe³

et al. 2004

Cancer Research

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Topoisomerase I inhibitors, such as CPT-11, are potent anticancer drugs against neuroblastoma (NB). Differentiating agents, such as retinoids, improve the survival of children with metastatic NB. To characterize the biological effects associated with exposure to CPT-11 in vivo, athymic mice bearing a human NB xenograft, named IGR-NB8 and characterized as an immature NB with poor prognostic markers, were treated with CPT-11. Prolonged stable disease was observed, resulting in an overall tumor growth delay of 115 days. During treatment, tumors differentiated into ganglioneuroblastomas (GGNB), which reverted into an immature phenotype when treatment was discontinued. In contrast, 13-cis retinoic acid failed to induce differentiation of IGR-NB8 in vivo. Tumor differentiation was associated with decreased N-myc expression, induction of p73 expression in the perinuclear area and cytoplasm, and a dramatic 35-fold decrease in topoisomerase I (topo I) catalytic activity. The full-length M r 100,000 topo I protein was present in both pre and post-treatment immature NB xenografts. In contrast, differentiated GGNBs did not contain the M r 100,000 protein but an intense M r 48,000 topo I fragment. Furthermore, redistribution of the M r 48,000 and 68,000 forms to the cytoplasm was observed in differentiated tumors. The same pattern of topo I expression and catalytic activity was observed in NBs and GGNBs obtained from pediatric patients. Our data suggest that prolonged in vivo exposure to CPT-11 induces differentiation of NB xenografts, which is associated with truncation of the topo I enzyme, relocation of the degraded forms to the cytoplasm, and decreased catalytic activity.

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Combined RARα- and RXR-specific ligands overcome N-myc-associated retinoid resistance in neuroblastoma cells

Cited by 22 publications

References 32 publications

The calcium‐sensing receptor and parathyroid hormone‐related protein are expressed in differentiated, favorable neuroblastic tumors

The calcium‐sensing receptor and parathyroid hormone‐related protein are expressed in differentiated, favorable neuroblastic tumors

The retinoid anticancer signal: mechanisms of target gene regulation

In Vivo Treatment with CPT-11 Leads to Differentiation of Neuroblastoma Xenografts and Topoisomerase I Alterations

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