Analysis of the oxidative catabolism of retinoic acid in rat Dunning R3327G prostate tumors

Krekels, Marita D.W.G.; Zimmerman, Jacco; Janssens, Boudewijn; Ginckel, R. Van; Cools, W.; Hove, Carl Van; Coene, Marie‐Claire; Wouters, Walter

doi:10.1002/(sici)1097-0045(199607)29:1<36::aid-pros5>3.3.co;2-2

Cited by 3 publications

(4 citation statements)

References 11 publications

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“…The activity of liarozole-fumarate (0.44 [tM) was only slightly lower than that of all-trans-RA. This IC50 value is similar to those reported previously for liarozole-fumarate in rat Dunning R3327G tumour homogenates (0.26 FtM) and rat liver homogenates (0.14 [tM) (Krekels et al, 1995). Taken together, the results presented here show that all-trans-RA catabolism can be induced by natural as well as synthetic retinoids and that induction is a receptor-mediated process.…”

Section: Discussionsupporting

confidence: 91%

“…Retinoic acid catabolism has also been shown in N-methyl-N-nitrosourea-induced mammary tumours in the rat (Bhat and Lacroix, 1989), F9 teratocarcinoma cells (Williams and Napoli, 1985) and LLC-PK1 cells (Napoli, 1986). Recently all-trans-RA catabolism was further demonstrated in MCF-7 breast cancer cells and rat Dunning R3327G prostate tumour homogenates (Krekels et al, 1995). In vivo catabolism of all-trans-RA has been extensively documented in rodents (Hanni et al, 1976;Hanni and Bigler, 1977;Frolik et al, 1980 (Dijkman et al, 1994;Smets et al, 1995) and in prostate cancer patients (Mahler et al, 1993 (Muindi et al, 1992), suggesting that all-trans-RA induces its own catabolism.…”

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confidence: 99%

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

Krekels

Verhoeven²,

Dun³

et al. 1997

Br J Cancer

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Cytochrome P450-dependent oxidation is a pathway for all-trans-retinoic acid (all-trans-RA) catabolism. Induction of this catabolic pathway was studied in MCF-7 breast cancer cells. MCF-7 cells showed low constitutive all-trans-RA catabolism. Concentration-dependent induction was obtained by preincubation of the cells with all-trans-RA (10(-9) to 10(-6) M). Onset of induction was fast, being detectable within 60 min, with maximal induction (45-fold) obtained after 16 h. Enzymatic characterization of induced all-trans-RA catabolism showed an estimated Km value (Michaelis-Menten constant) of 0.33 microM and a Vmax value (maximal velocity of an enzyme-catalysed reaction) of 54.5 fmol polar all-trans-RA metabolites 10(6) cells(-1) h(-1). These kinetic parameters represent the overall formation of polar metabolites from all-trans-RA. Induction of all-trans-RA catabolism was also obtained with other retinoids, CH55 >> 13-cis-RA = all-trans-RA > 9-cis-RA > 4-keto-all-trans-RA > 4-keto-13-cis-RA > retinol. The potency of the retinoids to induce all-trans-RA catabolism was correlated to their retinoic acid receptor affinity (Crettaz et al, 1990; Repa et al, 1990; Sani et al, 1990). Induction of all-trans-RA catabolism was inhibited by actinomycin D. Furthermore, all-trans-RA did not increase cytosolic retinoic acid-binding protein (CRABP) mRNA levels. These data suggest that induction of all-trans-RA catabolism in MCF-7 cells is a retinoic acid receptor-mediated gene transcriptional event. Induced all-trans-RA catabolism was inhibited by various retinoids with decreasing potency in the order: all-trans-RA > 4-keto-all-trans-RA > 13-cis-RA > 9-cis-RA > 4-keto-13-cis-RA > retinol > CH55. The antitumoral compound liarozole-fumarate inhibited all-trans-RA catabolism with a potency similar to that of all-trans-RA. Images Figure 4

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

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

Krekels

Verhoeven²,

Dun³

et al. 1997

Br J Cancer

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“…131 In in vivo studies using rats, oral liarozole at a dose of 5 or 20 mg/kg increased endogenous plasma tRA levels from Ͻ 0.5 ng/mL to 1.4 and 2.9 ng/mL, respectively. 66 Smets et al reported that liarozole increased plasma and tumor RA levels in the Dunning AT-6sq androgen-independent prostate carcinoma model in a dose-dependent manner.…”

Section: Effect On Endogenous Ra Levelsmentioning

confidence: 99%

The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer

Miller

1998

Cancer

133

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“…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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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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Analysis of the oxidative catabolism of retinoic acid in rat Dunning R3327G prostate tumors

Abstract: ABSTRACT:We studied the enzymatic characteristics of the oxidative catabolism of retinoic acid (RA)

Cited by 3 publications

References 11 publications

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

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

The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer

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

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