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Comparative Study
. 2002 Feb 12;86(4):605-11.
doi: 10.1038/sj.bjc.6600056.

Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity

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Free PMC article
Comparative Study

Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity

J Van Heusden et al. Br J Cancer. .
Free PMC article

Abstract

All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-trans-retinoic acid in the treatment of cancer is significantly hampered by its toxicity and the prompt emergence of resistance, believed to be caused by increased all-trans-retinoic acid metabolism. Inhibitors of all-trans-retinoic acid metabolism may therefore prove valuable in the treatment of cancer. In this study, we characterize R116010 as a new anticancer drug that is a potent inhibitor of all-trans-retinoic acid metabolism. In vitro, R116010 potently inhibits all-trans-retinoic acid metabolism in intact T47D cells with an IC(50)-value of 8.7 nM. In addition, R116010 is a selective inhibitor as indicated by its inhibition profile for several other cytochrome P450-mediated reactions. In T47D cell proliferation assays, R116010 by itself has no effect on cell proliferation. However, in combination with all-trans-retinoic acid, R116010 enhances the all-trans-retinoic acid-mediated antiproliferative activity in a concentration-dependent manner. In vivo, the growth of murine oestrogen-independent TA3-Ha mammary tumours is significantly inhibited by R116010 at doses as low as 0.16 mg kg(-1). In conclusion, R116010 is a highly potent and selective inhibitor of all-trans-retinoic acid metabolism, which is able to enhance the biological activity of all-trans-retinoic acid, thereby exhibiting antitumour activity. R116010 represents a novel and promising anticancer drug with an unique mechanism of action.

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Figures

Figure 1
Figure 1
Chemical structure of R116010, [S-(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]-2-benzothiazolamine.
Figure 2
Figure 2
Reverse-phase HPLC analysis of radiolabelled RA metabolites formed in T47D human breast cancer cells. T47D human breast cancer cells were cultured under basal culture conditions (A) or pretreated with 1 μM RA (B, C). Then, cells were collected and incubated with 0.1 μM [3H]RA, either in the absence (A, B) or presence (C) of 1 μM R116010. Supernatants were analyzed by reverse-phase HPLC (10).
Figure 3
Figure 3
Inhibition of RA metabolism by R116010 and liarozole-fumarate. T47D human breast cancer cells were pretreated with 1 μM RA to induce RA metabolism. Concentration-response curves showing the inhibition by R116010 (○) and liarozole-fumarate (•) were determined using the microcolumn assay as described in Materials and Methods. Results are presented as mean±s.d. for R116010 (n=4) and liarozole-fumarate (n=3).
Figure 4
Figure 4
RT–PCR analysis of CYP26A1 mRNA expression after treatment with RA. T47D human breast cancer cells were treated with various concentrations of RA for indicated time periods. Thereafter, total RNA was prepared and subjected to RT–PCR. Amplified products were analyzed by agarose gel electrophoresis with ethidium bromide staining.
Figure 5
Figure 5
Concentration-response curves showing the antiproliferative effects of (A) RA (□), R116010 (▪) and RA in combination with R116010 (•: 0.01 μM; ○: 0.1 μM; ▴: 1 μM) or (B) RA (□), liarozole-fumarate (▪) and RA in combination with liarozole-fumarate (•: 0.1 μM; ○: 1 μM; ▴: 10 μM) in T47D cells. Cell proliferation was measured after 7 days using a MTT-based assay as described in detail in Materials and Methods. Results are presented as mean±s.d. for R116010 (n=4) and liarozole-fumarate (n=3).
Figure 6
Figure 6
In vivo antitumour activity of RA (A) and R116010 (B) in the murine TA3-Ha tumour model. TA3-HA mammary carcinoma cells (1.5×106) were subcutaneously inoculated in mice. RA (A) or R116010 (B) was given by oral treatment twice daily from day 1 until day 21. Tumours were excised 24 h after the last treatment and weighed. Data are represented as box plots showing median group value, 25/75th percentile, 10/90th percentile and outliers. Groups were statistically compared to the vehicle-treated groups using the Mann–Whitney U-test. Statistical significance was defined at the level of *P<0.05.

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