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

Pettersson, Filippa; Colston, Kay W.; Dalgleish, Angus

doi:10.1054/bjoc.2000.1281

Cited by 60 publications

(35 citation statements)

References 42 publications

(38 reference statements)

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“…Moreover, authentic retinoid receptor-interacting ligands, including all-trans retinoic acid, also induce caspase-associated apoptosis in pancreatic cancer cells (Fujimoto et al, 1999;Pettersson et al, 2000Pettersson et al, , 2001. Some studies also show that an altered Bcl-2/Bax ratio, in favor of Bax, is associated with RRM-dependent cell death (Pettersson et al, 2000). However, the Bcl-2/Bax ratio was not observed to change in the present studies, suggesting that this change is not necessary for the effects of AGN193198.…”

Section: Role Of Apoptosiscontrasting

confidence: 41%

“…This is perhaps not surprising, since, as outlined above, apoptosis is a hallmark of the mechanism of RRM action. Moreover, authentic retinoid receptor-interacting ligands, including all-trans retinoic acid, also induce caspase-associated apoptosis in pancreatic cancer cells (Fujimoto et al, 1999;Pettersson et al, 2000Pettersson et al, , 2001. Some studies also show that an altered Bcl-2/Bax ratio, in favor of Bax, is associated with RRM-dependent cell death (Pettersson et al, 2000).…”

Section: Role Of Apoptosismentioning

confidence: 99%

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A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

2005

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acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)-or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR-or RXR receptorselective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclindependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.

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Section: Role Of Apoptosiscontrasting

confidence: 41%

Section: Role Of Apoptosismentioning

confidence: 99%

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

2005

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“…We have shown that they can also act as potent apoptosis-inducers (Pettersson et al, 2000), and in this study we have further elucidated the mechanisms behind this finding.…”

Section: Discussionmentioning

confidence: 52%

“…A phase II trial of 13-cis retinoic acid and interferon-a in patients with advanced pancreatic carcinoma has also been completed and promising results with one partial remission and 14 out of 22 patients with stable disease for a median duration of 5 months were reported (Brembeck et al, 1998). We have shown that ATRA and 9cRA induce apoptosis in a number of pancreatic adenocarcinoma cell lines and enhance the cytotoxic effects of chemotherapeutic agents in these cells (Pettersson et al, 2000(Pettersson et al, , 2001. In the present study, we examined the role of two families of proteins that are important players in many apoptotic responses, the Bcl-2 proteins and caspases.…”

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confidence: 87%

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

et al. 2002

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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-cisretinoic 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-g is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-g selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-g is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-b/ g 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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“…In vivo studies in animal models have shown that seocalcitol can cause regression of established tumours, prevent the development of metastases, and prolong survival time in tumour-bearing animals (Colston et al, 1992(Colston et al, , 1997James et al, 1998;Lokeshwar et al, 1999;Nickerson and Huynh, 1999), with significant inhibition of tumour progression achieved at doses that do not cause significant hypercalcaemia (Colston et al, 1992). Furthermore, seocalcitol inhibits growth of pancreatic cancer cells in vitro (Zugmaier et al, 1996;Pettersson et al, 2000) and inhibits growth in vivo of pancreatic cancer xenografts in immunodeficient mice (Colston et al, 1997). Seocalcitol was well tolerated in a phase I clinical study in patients with breast or colorectal cancer, with dose-dependent hypercalcaemica (Gulliford et al, 1998).…”

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confidence: 99%

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

et al. 2002

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Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo . Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10–15 μg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82–532 days (median=168 days). The time to treatment failure ( n =36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states. British Journal of Cancer (2002) 86 , 680–685. DOI: 10.1038/sj/bjc/6600162 www.bjcancer.com © 2002 Cancer Research UK

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

Cited by 60 publications

References 42 publications

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

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

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

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