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Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax.

Pettersson F, Dalgleish AG, Bissonnette RP, Colston KW - Br. J. Cancer (2002)

Bottom Line: Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid.A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner.Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London SW17 ORE, UK.

ABSTRACT
All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-gamma is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

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Related in: MedlinePlus

LG101093 and LGD1550 induce apoptosis in T3M-4 cells as determined by the Cell Death Detection ELISA. Cells were treated for 6 days with 10 nM of LGD1550 and 500 nM of each of the other compounds. (B) The RAR-β/γ selective antagonist LG030403 inhibits apoptosis induced by 9cRA and LGD1550. Cells were treated for 6 days with 500 nM 9cRA or 10 nM LGD1550, with or without 500 nM LG030403. Results are means±s.d. (n=4). ### Indicates a significant difference compared to agonist alone (P<0.005).
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fig8: LG101093 and LGD1550 induce apoptosis in T3M-4 cells as determined by the Cell Death Detection ELISA. Cells were treated for 6 days with 10 nM of LGD1550 and 500 nM of each of the other compounds. (B) The RAR-β/γ selective antagonist LG030403 inhibits apoptosis induced by 9cRA and LGD1550. Cells were treated for 6 days with 500 nM 9cRA or 10 nM LGD1550, with or without 500 nM LG030403. Results are means±s.d. (n=4). ### Indicates a significant difference compared to agonist alone (P<0.005).

Mentions: Using the Cell Death Detection ELISA, it was confirmed that LG101093 and LGD1550 induce apoptosis in T3M-4 cells, causing significant nuclear fragmentation. Neither of the other compounds had this effect. Again, LGD1550 was significantly more potent, causing the same level of apoptosis as LG101093 and 9cRA at a 50-fold lower concentration (Figure 8A,BFigure 8


Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax.

Pettersson F, Dalgleish AG, Bissonnette RP, Colston KW - Br. J. Cancer (2002)

LG101093 and LGD1550 induce apoptosis in T3M-4 cells as determined by the Cell Death Detection ELISA. Cells were treated for 6 days with 10 nM of LGD1550 and 500 nM of each of the other compounds. (B) The RAR-β/γ selective antagonist LG030403 inhibits apoptosis induced by 9cRA and LGD1550. Cells were treated for 6 days with 500 nM 9cRA or 10 nM LGD1550, with or without 500 nM LG030403. Results are means±s.d. (n=4). ### Indicates a significant difference compared to agonist alone (P<0.005).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2376147&req=5

fig8: LG101093 and LGD1550 induce apoptosis in T3M-4 cells as determined by the Cell Death Detection ELISA. Cells were treated for 6 days with 10 nM of LGD1550 and 500 nM of each of the other compounds. (B) The RAR-β/γ selective antagonist LG030403 inhibits apoptosis induced by 9cRA and LGD1550. Cells were treated for 6 days with 500 nM 9cRA or 10 nM LGD1550, with or without 500 nM LG030403. Results are means±s.d. (n=4). ### Indicates a significant difference compared to agonist alone (P<0.005).
Mentions: Using the Cell Death Detection ELISA, it was confirmed that LG101093 and LGD1550 induce apoptosis in T3M-4 cells, causing significant nuclear fragmentation. Neither of the other compounds had this effect. Again, LGD1550 was significantly more potent, causing the same level of apoptosis as LG101093 and 9cRA at a 50-fold lower concentration (Figure 8A,BFigure 8

Bottom Line: Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid.A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner.Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London SW17 ORE, UK.

ABSTRACT
All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-gamma is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

Show MeSH
Related in: MedlinePlus