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

Abstract

All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-transretinoic 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 71 . 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.

Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice

“…superior to the effects observed with R116010 in human breast T47D cancer cells (Van Heusden et al, 2002). In the latter study, R116010, at a concentration of 1 mM, enhanced the antiproliferative activity of ATRA only by threefold.…”

“…Although a first generation RAMBA, liarozole has been shown to exhibit potent antitumour efficacy against human androgen-independent PCA tumours, such as PC-3ML-B (Stearns et al, 1993), and DU-145 (Smets et al, 1994) and several rat PCA tumours (De Coster et al, 1992;Dijkman et al, 1994); this study appears to be the first report on the antitumour efficacy of RAMBAs against human androgen-dependent LNCaP PCA tumours. Recently, it was demonstrated that a second generation RAMBA, R116010, was able to significantly inhibit the growth of murine TA3-Ha mammary tumours in A/J mice (Van Heusden et al, 2002). Given that our RAMBAs exhibited potent in vitro antiproliferative activities, their in vivo antitumour efficacies are rather disappointing.…”

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

“…A dose of 66.0 mmol kg À1 day À1 caused a reduction of 92.6% in the mean final tumour weight compared with that of tumour-bearing mice receiving vehicle alone, with no apparent toxicity as there was no change in body weight of the mice. It was recently reported that the growth of murine oestrogen-independent TA3-Ha mammary tumours were significantly inhibited by a non-retinoidal RAMBA, R116010 (Van Huesden et al, 2002). The study demonstrated the antitumour efficacy of R116010 in an oestrogen-independent model of un-established tumours and it is not clear if the agent is effective against oestrogen-dependent breast tumours.…”

A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma

“…Similarly, in vitro inhibition of CYP26 leads to an increase in differentiation, decrease in proliferation, cell adhesion and metastatic potential. This has led to the suggestion of a possible chemoprevention role of using specific CYP26 inhibitors (Wouters et al, 1992;Van Heusden et al, 2002). In addition, RA metabolism-blocking agents lead to a reduction of tumour size in mouse xenograft models (Patel et al, 2004).…”