Induction of the oxidative catabolism of retinoic acid in MCF-7 cells

Krekels, Marita D.W.G.; Verhoeven, Arthur J.; Dun, Jacky Van; Cools, W.; Hove, Carl Van; Dillen, Lieve; Coene, M.‐C.; Wouters, Walter

doi:10.1038/bjc.1997.190

Cited by 15 publications

(19 citation statements)

References 49 publications

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“…Retinol, a possible source of RA, was harder to extract and about 40% could not be removed. We assumed that the remaining amount of retinol did not interfere with our results as MCF-7 cells are unable to convert retinol into ATRA (Krekels et al, 1997).…”

Section: Discussionmentioning

confidence: 96%

“…ATRA catabolism, under the present culture conditions, was induced to the same extent, as described previously (Wouters et al, 1992;Krekels et al, 1997). Only the supematant was analysed for the presence of ATRA metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…Confluent MCF-7 cells, cultured in medium containing 5% DCCtreated FBS, were treated for 24 h with 106 M ATRA to induce ATRA catabolism (Wouters et al, 1992;Krekels et al, 1997). Cells were then washed twice with 25 ml of culture medium, trypsinized and harvested.…”

Section: Hplc Analysismentioning

confidence: 99%

“…Oxidative catabolism of RA to more polar metabolites was observed in N-methyl-N-nitrosourea-induced mammary tumours in the rat (Bhat and Lacroix, 1989), in rat Dunning R3327G prostate tumours (Krekels et al, 1996), F9 mouse teratocarcinoma cells (Williams and Napoli, 1985), LLC-PK1 pig kidney cancer cells (Napoli, 1986), BA-HAN-IC rat rhabdomyosarcoma cells (Biesalski et al, 1990), as well as in the human breast cancer cells MCF-7 (Wouters et al, 1992;Krekels et al, 1997) and T47D (Han and Choi, 1996).…”

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confidence: 99%

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All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

heusden

Wouters²,

Ramaekers³

et al. 1998

Br J Cancer

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Summary All-trans-retinoic acid (ATRA) is well known to inhibit the proliferation of human breast cancer cells. Much less is known about the antiproliferative activity of the naturally occurring metabolites and isomers of ATRA. In the present study, we investigated the antiproliferative activity of ATRA, its physiological catabolites 4-oxo-ATRA and 5,6-epoxy-ATRA and isomers 9-cis-RA and 1 3-cis-RA in MCF-7 human breast cancer cells by bromodeoxyuridine incorporation. MCF-7 cells were grown in steroid-and retinoid-free medium supplemented with growth factors. Under these culture conditions, ATRA and its naturally occurring catabolites and isomers showed significant antiproliferative activity in MCF-7 cells in a concentration-dependent manner (10-11 M to 10-M). The antiproliferative activity of ATRA catabolites and isomers was equal to that of the parent compound ATRA at concentrations of 10-M and 1 07 M. Only at 10-6 M were the catabolites and the stereoisomer 1 3-cis-RA less potent. The stereoisomer 9-cis-RA was as potent as ATRA at all concentrations tested (1 0-11 M to 10-M). In addition, we show that the catabolites and isomers were formed from ATRA to only a limited extent. Together, our findings suggest that in spite of their high antiproliferative activity the catabolites and isomers of ATRA cannot be responsible for the observed growth inhibition induced by ATRA.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Hplc Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

heusden

Wouters²,

Ramaekers³

et al. 1998

Br J Cancer

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“…The Microcolumn assay for ATRA catabolism ATRA catabolism was quantitatively determined using the microcolumn assay as described previously (Krekels et al, 1997). Briefly, cells cultured in medium containing 5% DCC-treated FBS, were pretreated for 24 h with I06 M ATRA to induce the ATRA catabolic pathway ; Krekels et al, 1997).…”

Section: Bromodeoxyuridine (Brdu) Detectionmentioning

confidence: 99%

The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells

heusden

Wouters²,

Ramaekers³

et al. 1998

Br J Cancer

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SummaryThe clinical use of all-trans-retinoic acid (ATRA) in the treatment of cancer is significantly hampered by the prompt emergence of resistance, believed to be caused by increased ATRA catabolism. Inhibitors of ATRA catabolism may therefore prove valuable for cancer therapy. Liarozole-fumarate is an anti-tumour drug that inhibits the cytochrome P450-dependent catabolism of ATRA. ATRA, but also its naturally occurring catabolites, 4-oxo-ATRA and 5,6-epoxy-ATRA, as well as its stereoisomers, 9-cis-RA and 13-cis-RA, show significant antiproliferative activity in MCF-7 human breast cancer cells. To further elucidate its mechanism of action, we investigated whether liarozolefumarate was able to enhance the antiproliferative activity of ATRA catabolites and isomers. Liarozole-fumarate alone up to a concentration of 10-6 M had no effect on MCF-7 cell proliferation. However, in combination with ATRA or the ATRA catabolites, liarozole-fumarate (1 06 M) significantly enhanced their antiproliferative activity. On the contrary, liarozole-fumarate (1 0-6 M) was not able to potentiate the antiproliferative activity of the ATRA stereoisomers, most probably because of the absence of cytochrome P450-dependent catabolism. Together, these findings show that liarozole-fumarate acts as a versatile inhibitor of retinoid catabolism in that it not only blocks the breakdown of ATRA, but also inhibits the catabolic pathway of 4-oxo-ATRA and 5,6-epoxy-ATRA, thereby enhancing their antiproliferative activity.

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Discovery of Inhibitors of MCF‐7 Tumor Cell Adhesion to Endothelial Cells and Investigation on their Mode of Action

Bild

Jose

Hartmann

2004

Archiv der Pharmazie

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Metastasis, the main reason for high mortality of cancer, is a multistep process. One important step in this process is the adhesion of tumor cells to vascular endothelium at sites distant from primary tumors during hematogenous dissemination. In order to investigate and quantify the adhesion of tumor cells to endothelial cells we developed an in vitro model using MCF-7 breast cancer cells and monolayers of human umbilical vein endothelial cells (HUVEC). The tumor cells were specifically labeled with a fluorescent dye for quantification; for increasing the amount of adherent cells, HUVEC monolayers were stimulated with phorbol ester before the addition of the tumor cells. Due to previous reports that products of several P450 enzymes contribute to the progression of certain kinds of cancer, inhibitors of CYP5 (thromboxane A(2) synthase), CYP17 (17alpha-hydroxylase-C17, 20-lyase), and CYP19 (aromatase) were tested in this in vitro model for their potency to reduce cancer cell adhesion. Within each series of P450 inhibitors, compounds with high inhibitory activity on tumor cell adhesion were identified. At an initial concentration of 100 microM, BW26, a potent inhibitor of CYP5, reduced tumor cell adhesion of MCF-7 to HUVECs to 15%, BW40 (CYP17) to 29%, and SU5a (CYP19) to 11% of the corresponding controls (no inhibitor). Reduction of tumor cell adhesion was shown to occur in a concentration-dependent manner. In addition to these inhibitors of CYP5, CYP17, and CYP19, liarozole, known to be a potent inhibitor of CYP26 (retinoic acid-4-hydroxylase) and ATRA (all-trans-retinoic acid) metabolism, was able to reduce tumor cell adhesion to 51% of the initial rate. Experiments elucidating the mode of action of these compounds revealed that inhibition of the mentioned CYP enzymes is not responsible for their ability to reduce tumor cell adhesion.

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Induction of the oxidative catabolism of retinoic acid in MCF-7 cells

Cited by 15 publications

References 49 publications

All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells

Discovery of Inhibitors of MCF‐7 Tumor Cell Adhesion to Endothelial Cells and Investigation on their Mode of Action

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