pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

Panigone, Silvia; Debernardi, Silvana; Fontanella, Enrico; Airoldi, Rita; Delia, Domenico

doi:10.1038/sj.onc.1203743

Cited by 29 publications

(21 citation statements)

References 40 publications

(65 reference statements)

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“…It has been reported that 4-HPR and 4OH-Tam downmodulate transcription of Cyclin D1 (Panigone et al, 2000). Therefore, it is possible that the expression of Cyclin D1 from a heterologous promoter that is not subjected to the repression by these drugs may render the rhabdoid cells less susceptible for the drug-mediated cytotoxicity.…”

Section: Expression Of Cyclin D1 From a Heterologous Promoter Rendersmentioning

confidence: 99%

Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors

et al. 2005

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Rhabdoid tumors (RTs) are aggressive and currently incurable pediatric malignancies. INI1/hSNF5 is a tumor suppressor biallelically inactivated in RTs. Our previous studies have indicated that cyclin D1 is a key downstream target of INI1/hSNF5 and genesis and/or survival of RTs in vivo is critically dependent on the presence of cyclin D1. In this report, we have tested the hypothesis that therapeutic targeting of cyclin D1 is an effective means of treating RTs. We found that RNA interference of cyclin D1 in rhabdoid cells was sufficient to induce G1 arrest and apoptosis. Furthermore, we found that pharmacological intervention with low micromolar concentrations of N-(4-hydroxyphenyl)retinamide (4-HPR), which downmodulates cyclin D1, induced G1 arrest and apoptosis in rhabdoid cell lines. 4-HPR in combination with 4-hydroxy-tamoxifen (4OH-Tam), synergistically inhibited survival as well as anchorage-dependent and -independent growth of rhabdoid cells and caused synergistic induction of cell cycle arrest and apoptosis. 4-HPR and tamoxifen exhibited synergistic growth inhibition of RTs in xenograft models in vivo. The effects of combination of drugs were correlated to the depletion of cyclin D1 levels both in in vitro and in vivo tumor models. These results demonstrate that 4-HPR and tamoxifen are effective chemotherapeutic agents for RTs. We propose that downmodulation of cyclin D1 is a novel and effective therapeutic strategy for RTs.

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Section: Expression Of Cyclin D1 From a Heterologous Promoter Rendersmentioning

confidence: 99%

Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors

et al. 2005

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“…Treatment with 4-HPR exerts restrictions on the cell cycle regulating cyclin dependent kinase (CDK) pathway [12] and phosphorylation of retinoblastoma protein (pRb), whose dephosphorylation results in cell cycle arrest. Inhibition of cell cycle check points would prolong the duration of cell cycle arrest, contributing to cytokine mediated activation of intrinsic apoptotic pathway.…”

Section: Introductionmentioning

confidence: 99%

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

2008

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Glioblastoma is the most malignant and prevalent brain tumor in humans. It is composed of heterogenic abnormal astroglial cells that avoid differentiation, maintain proliferation, and reluctant to apoptosis. N-(4-Hydroxyphenyl) retinamide (4-HPR) induced astrocytic differentiation and increased sensitivity to interferon-gamma (IFN-γ) for apoptosis in human glioblastoma A172, LN18, and SNB19 cells. Combination of 4-HPR and IFN-γ significantly inhibited human telomerase reverse transcriptase (hTERT), cyclin dependent kinase 2 (CDK2), and survivin to upregulate caspase-8, caspase-9, and caspase-3 for increasing apoptosis in all glioblastoma cell lines. Hence, combination of 4-HPR and IFN-γ should be considered for controlling growth of different human glioblastoma cells.

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“…Current experimental data suggest that fenretinide induces inhibitory effects by both receptor-dependent and -independent mechanisms (Sheikh et al 1995, Fanjul et al 1996, Sun et al 1999. These mechanisms include both an increase in the expression of RAR-b and a decrease in the expression of cell cycle modulators, such as cyclin D and cyclin-dependent kinases, in different cancer cell lines, including breast cancer cells (Liu et al 1998, Panigone et al 2000.…”

Section: The Synthetic Retinoid Fenretinidementioning

confidence: 99%

Clinical trials with retinoids for breast cancer chemoprevention

Zanardi¹,

Serrano²,

Argusti³

et al. 2006

Endocr Relat Cancer

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Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGFbinding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.

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pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

Cited by 29 publications

References 40 publications

Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors

Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

Clinical trials with retinoids for breast cancer chemoprevention

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