Thiantanawat Apinya, Long Brian J, Brodie Angela M
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Health Science Facility, Room 580G, 685 West Baltimore Street, Baltimore, MD 21201, USA.
Cancer Res. 2003 Nov 15;63(22):8037-50.
Aromatase inhibitors have recently been reported to be more effective than the antiestrogen tamoxifen (Tam) in treating breast cancer. Here, we studied the mechanisms and signaling pathways of cell growth, cell cycle progression, and apoptosis induced by three aromatase inhibitors: letrozole (Let), anastrozole, and 4-hydroxyandrostenedione in comparison with estrogen withdrawal (E2W) and antiestrogens Tam and faslodex. Estrogen-dependent human breast cancer cells stably transfected with aromatase (MCF-7Ca) were used. All treatments induced growth suppression and cell cycle arrest at the G(0)-G(1) phase that was associated with up-regulation of p53 and p21 protein and mRNA levels and down-regulation of cyclin D1 and c-myc mRNA. The apoptotic index was increased 4-7 fold, Bcl-2 protein expression decreased, Bax increased, and caspase-9, caspase-6, and caspase-7 were activated but not caspase-3 and caspase-8. Let and E2W caused regression of tumors of MCF-7Ca cells grown in nude mice and increased the number of cells undergoing apoptosis. In contrast, Tam and faslodex did not induce tumor regression and a lower number of apoptotic cells was detected. Cleavage of poly(ADP-ribose) polymerase was detected. Treatment with Let, Tam, or E2W resulted in a dose- and time-dependent increase in active caspase-7 and up-regulation of p53 and p21 protein. Although the mechanisms involved appeared to be similar for antiestrogens and aromatase inhibitors, the most significant effects occurred with Let, which were significantly greater than with E2W and consistent with marked effects of Let on tumor and cell growth.
最近有报道称，芳香化酶抑制剂在治疗乳腺癌方面比抗雌激素他莫昔芬（Tam）更有效。在此，我们研究了三种芳香化酶抑制剂（来曲唑（Let）、阿那曲唑和4-羟基雄烯二酮）与雌激素撤药（E2W）以及抗雌激素Tam和氟维司群相比，诱导细胞生长、细胞周期进程和凋亡的机制及信号通路。使用稳定转染芳香化酶的雌激素依赖性人乳腺癌细胞（MCF-7Ca）。所有处理均诱导生长抑制和细胞周期停滞于G(0)-G(1)期，这与p53和p21蛋白及mRNA水平上调以及细胞周期蛋白D1和c-myc mRNA下调有关。凋亡指数增加4 - 7倍，Bcl-2蛋白表达降低，Bax增加，半胱天冬酶-9、半胱天冬酶-6和半胱天冬酶-7被激活，但半胱天冬酶-3和半胱天冬酶-8未被激活。Let和E2W导致裸鼠体内生长的MCF-7Ca细胞肿瘤消退，并增加凋亡细胞数量。相比之下，Tam和氟维司群未诱导肿瘤消退，且检测到的凋亡细胞数量较少。检测到聚（ADP-核糖）聚合酶的裂解。用Let/Tam或E2W处理导致活性半胱天冬酶-7呈剂量和时间依赖性增加以及p53和p21蛋白上调。尽管抗雌激素和芳香化酶抑制剂涉及的机制似乎相似，但Let产生的最显著作用明显大于E2W，且与Let对肿瘤和细胞生长的显著作用一致。
