Retinoid-induced apoptosis in normal and neoplastic tissues

Nagy, László; Thomázy, Vilmos; Heyman, Richard A.; Davies, Peter J.

doi:10.1038/sj.cdd.4400337

Cited by 111 publications

(66 citation statements)

References 64 publications

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“…1 These compounds have been shown to have antitumor activity in several experimental models and they are being evaluated as therapeutic and preventive agents for malignant diseases. 2 Fenretinide or N-(4-hydroxyphenyl)retinamide (HPR) is a retinoic acid (RA) derivative that has shown lower toxicity than other retinoids while maintaining antitumor activity against various tumor types.…”

Section: Introductionmentioning

confidence: 99%

Involvement of c-Fos in fenretinide-induced apoptosis in human ovarian carcinoma cells

et al. 2003

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Fenretinide (HPR), a synthetic retinoid that exhibits lower toxicity than other retinoids, has shown preventive and therapeutic activity against ovarian tumors. Although the growth inhibitory effects of HPR have been ascribed to its ability to induce apoptosis, little is known about the molecular mechanisms involved. Since the proto-oncogene c-Fos has been implicated in apoptosis induction, we analyzed its role in mediating HPR response in a human ovarian carcinoma cell line (A2780) sensitive to HPR apoptotic effect. In these cells, HPR treatment caused induction of c-Fos expression, whereas such an effect was not observed in cells made resistant to HPR-induced apoptosis (A2780/HPR). Moreover, in a panel of other human ovarian carcinoma cell lines, c-Fos inducibility and HPR sensitivity were closely associated. Ceramide, which is involved in HPR-induced apoptosis, was also involved in cFos induction because its upregulation by HPR was reduced by fumonisin B 1 , a ceramide synthase inhibitor. The causal relationship between c-Fos induction and apoptosis was established by the finding of an increased apoptotic rate in cells overexpressing c-Fos. Similarly to that observed for c-Fos expression, HPR treatment increased c-Jun expression in HPR-sensitive but not in HPR-resistant cells, suggesting the involvement of the transcription factor activating protein 1 (AP-1) in HPR-induced apoptosis. In gene reporter experiments, HPR stimulated AP-1 transcriptional activity and potentiated the AP-1 activity induced by 12-tetradecanoylphorbol 13-acetate. Furthermore, inhibition of AP-1 DNA binding, by transfecting A2780 cells with a dominantnegative Fos gene, caused decreased sensitivity to HPR apoptotic effects. Overall, the results indicate that c-Fos plays a role in mediating HPR-induced growth inhibition and apoptosis in ovarian cancer cells and suggest that c-Fos regulates these processes as a member of the AP-1 transcription factor.

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Section: Introductionmentioning

confidence: 99%

Involvement of c-Fos in fenretinide-induced apoptosis in human ovarian carcinoma cells

et al. 2003

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“…Studies of the anti-tumour actions of retinoids and vitamin D derivatives show that growth inhibition, cellular differentiation and/or apoptosis can be induced in a variety of cell types (Bollag et al, 1994;Lotan, 1996;Nagy et al, 1998). A major limitation to the use of 1,25D 3 in a therapeutic setting is its potent induction of hypercalcaemia, and to circumvent this problem synthetic analogues with a more favourable profile of activity have been developed.…”

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confidence: 99%

Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro

2000

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Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9- cis -retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth inhibitors. They were also more effective on their own than in combination with 9cRA. Growth arrest correlated with an increased proportion of cells in the G0/G1 phase. Apoptosis was induced in the three cell lines by 9cRA, whereas neither EB1089 nor CB1093 had this effect. Furthermore, addition of EB1089 or CB1093 together with 9cRA resulted in significantly reduced apoptosis. Our results show that retinoic acids as well as vitamin D analogues have inhibitory effects on pancreatic tumour cells but different and antagonistic mechanisms seem to be employed. © 2000 Cancer Research Campaign

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“…The original data were obtained thanks to the efforts of Peter Davies, who noted the induction of transglutaminase and the differentiation of monocytes and HL-60 cell line into macrophages during treatment with retinoids (Davies et al 1985;Nagy et al 1998). This phenomenon was accompanied by a marked induction of transglutaminase which occurred in vitro as well as in vivo in most cell types.…”

Section: The Years Of the Genementioning

confidence: 99%