Chetrite G, Paris J, Botella J, Pasqualini J R
Steroid Hormone Research Unit, Paris, France.
J Steroid Biochem Mol Biol. 1996 Aug;58(5-6):525-31. doi: 10.1016/0960-0760(96)00094-5.
It is well recognized that estradiol (E2) is one of the most important hormones supporting the growth and evolution of breast cancer. Consequently, to block this hormone before it enters the cancer cell or in the cell itself, has been one of the main targets in recent years. In the present study we explored the effect of the progestin, nomegestrol acetate, on the estrone sulfatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities of MCF-7 and T-47D human breast cancer cells. Using physiological doses of estrone sulfate (E1S: 5 x 10(-9)M), nomegestrol acetate blocked very significantly the conversion of E1S to E2. In the MCF-7 cells, using concentrations of 5 x 10(-6)M and 5 x 10(-5) M of nomegestrol acetate, the decrease of E1S to E2 was, respectively, -43% and -77%. The values were, respectively, -60% and -71% for the T-47D cells. Using E1S at 2 x 10(-6) M and nomegestrol acetate at 10(-5) M, a direct inhibitory effect on the enzyme of -36% and -18% was obtained with the cell homogenate of the MCF-7 and T-47D cells, respectively. In another series of studies, it was observed that after 24 h incubation of a physiological concentration of estrone (E1: 5 x 10(-9)M) this estrogen is converted in a great proportion to E2. Nomegestrol acetate inhibits this transformation by -35% and -85% at 5 x 10(-7)M and 5 x 10(-5)M, respectively in T-47D cells; whereas in the MCF-7 cells the inhibitory effect is only significant, -48%, at 5 x 10(-5)M concentration of nomegestrol acetate. It is concluded that nomegestrol acetate in the hormone-dependent MCF-7 and T-47D breast cancer cells significantly inhibits the estrone sulfatase and 17beta-HSD activities which converts E1S to the biologically active estrogen estradiol. This inhibition provoked by this progestin on the enzymes involved in the biosynthesis of E2 can open new clinical possibilities in breast cancer therapy.
众所周知，雌二醇（E2）是支持乳腺癌生长和进展的最重要激素之一。因此，在这种激素进入癌细胞之前或在细胞内阻断它，已成为近年来的主要目标之一。在本研究中，我们探讨了孕激素醋酸诺美孕酮对MCF-7和T-47D人乳腺癌细胞的硫酸雌酮酶和17β-羟类固醇脱氢酶（17β-HSD）活性的影响。使用生理剂量的硫酸雌酮（E1S：5×10⁻⁹M），醋酸诺美孕酮非常显著地阻断了E1S向E2的转化。在MCF-7细胞中，使用5×10⁻⁶M和5×10⁻⁵M浓度的醋酸诺美孕酮，E1S向E2的减少分别为-43%和-77%。T-47D细胞的值分别为-60%和-71%。使用2×10⁻⁶M的E1S和10⁻⁵M的醋酸诺美孕酮，对MCF-7和T-47D细胞的细胞匀浆中该酶的直接抑制作用分别为-36%和-18%。在另一系列研究中，观察到在生理浓度的雌酮（E1：5×10⁻⁹M）孵育24小时后，这种雌激素大部分转化为E2。在T-47D细胞中，醋酸诺美孕酮在5×10⁻⁷M和5×10⁻⁵M时分别抑制这种转化-35%和-85%；而在MCF-7细胞中，仅在5×10⁻⁵M浓度的醋酸诺美孕酮时抑制作用显著，为-48%。得出结论，在激素依赖性MCF-7和T-47D乳腺癌细胞中，醋酸诺美孕酮显著抑制将E1S转化为生物活性雌激素雌二醇的硫酸雌酮酶和17β-HSD活性。这种孕激素对参与E2生物合成的酶的抑制作用可为乳腺癌治疗开辟新的临床可能性。
