Retinoic acid (RA) is a metabolite of vitamin A1, which can regulate the function of vitamin A1 required for growth and development. Specifically, the antitumor effect of retinoids is attributed to their effects on cell proliferation, differentiation, apoptosis and angiogenesis. All trans-retinoic acid (ATRA) and other natural and synthetic retinoids regulate many important functions. Besides, ATRA is an effective differentiation agent, which is very important for development and can effectively prevent and treat cancer. Moreover, ATRA redirects cells to their normal phenotype, thereby improving tumor proliferation and invasion. ATRA also plays its role by inducing apoptosis. Furthermore, ATRA and its analogs have been studied in multiple systems as potential drugs for chemoprevention and treatment of a variety of cancers.

Meanwhile, ATRA is responsible for self-inducing cytochrome P450 dependent enzymes (ATRA 4-hydroxylase) present in different tissues and cancer cells. In addition to the potent inhibitors of ATRA metabolism, they also have inherent potent cancer anti-proliferative activity. Nonetheless, RAMBA is an abnormal effective inhibitor of ATRA metabolism in estrogen receptor-positive (ER+) breast cancer cells in vitro. Here, we will introduce an orally active RAMBA, Liarozole.

Liarozole is an Orally Active Retinoic Acid (RA) Metabolism-Blocking Agent (RAMBA).

To begin with, Liarozole is an imidazole derivative and orally active RAMBA. Importantly, Liarozole inhibits the cytochrome P450 (CYP26)-dependent 4-hydroxylation of retinoic acid (IC50=7 μM). Particularly, it results in increased tissue levels of retinoic acid. Liarozole shows antitumoral properties.

Next in importance, Liarozole with 0.01~10 μM for 9 days inhibits MCF-7 cells proliferation. Liarozole with 1 μM for 4 days completely inhibits chondrogenesis in mesenchymal cells. Obviously, Liarozole with 5-20 mg/kg by p.o. for 3 days reverses the vaginal keratosis caused by estrogen stimulation. Additionally, Liarozole reduces tumor burden substantially.

All in all, Liarozole is an imidazole derivative and orally active RAMBA.


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