Control of Sulfatase Activity by Nomegestrol Acetate in Normal and Cancerous Human Breast Tissues

Abstract

Nomegestrol acetate (NOMAC), a 17α-hydroxy-nor-progesterone derivative (17α-acetoxy-6-methyl-19-nor-4,6-pregnadiene-3,20-dione, the active substance in Lutenyl®), is a potent and useful clinical synthetic progestin for the treatment of menopausal complaints and is under current development for oral contraception. Previous studies in this laboratory demonstrated that NOMAC can block sulfatase and 17β-hydroxysteroid dehydrogenase, the enzymes involved in the biosynthesis and transformation of estradiol (E₂) in hormone-dependent MCF-7 and T-47D breast cancer cells. In the present study, the effect of NOMAC on sulfatase activity using total breast cancer tissue, compared to the effect in normal breast tissue, was explored. Slices of tumoral or normal breast tissues (45-65 mg) were incubated in buffer (20 mM Tris-HCl, pH 7.2) with physiological concentrations of [³H]-estrone sulfate (5×10^-9 M), alone or in the presence of nomegestrol acetate (5×10^-5 - 5×10^-7 - 5×10^-9 M), for 4 h at 37°C. Estrone sulfate (E₁S), estrone (E₁) and E₂ were characterized by thin layer chromatography and quantified using the corresponding standard. It was observed that [³H]- E₁S was only converted to [³H]- E₁ and not to [³H]- E₂, in normal or cancerous breast tissues, which suggests a low or no 17β-HSD activity under these experimental conditions. The sulfatase activity was more intense with breast cancer tissue than normal tissue, since the concentrations of E₁ were 42.5±3.4 and 27.2±2.5 pg/mg tissue, respectively. NOMAC, at the concentration of 5×10^-5 M, inhibited this conversion by 49.2% and 40.8% in cancerous and normal breast tissues, respectively. The sulfatase inhibition at low concentration (5×10^-7 M) was 32.5% and 22.8%, respectively. It is concluded that sulfatase activity is almost twice as potent in cancerous breast tissues than in normal tissues. Nomegestrol acetate is a strong anti-sulfatase agent, in particular with cancerous breast tissues. The inhibition of estrone sulfatase activity by NOMAC in total normal or cancerous breast tissues can open attractive perspectives for future clinical trials.