Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on letrozole-insensitive breast cancer cells
Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on letrozole-insensitive breast cancer cells
复制标题
DOI：
10.1158/0008-5472.can-06-2168
复制
发表时间：
2006-12-01
期刊：
影响因子：
11.2
通讯作者：
Njar, Vincent C. O.
中科院分区：
文献类型：
--
作者：
Belosay, Aashvini;Brodie, Angela M. H.;Njar, Vincent C. O.
芳香化酶抑制剂被证明是更有效的比他莫昔芬绝经后雌激素受体（ER）阳性乳腺癌。然而，不可避免地产生对治疗的抗药性是一个令人关切的问题。我们研究了新型维甲酸代谢阻断剂VN/14-1在克服来曲唑长期培养（LTLC）细胞对来曲唑耐药方面的作用。与稳定转染芳香化酶的MCF-7细胞（MCF-7 Ca）相比，LTLC细胞对芳香化酶抑制剂的生长抑制不再敏感。HER-2/磷酸化丝裂原活化蛋白激酶（pMAPK）生长因子信号通路被激活，乳腺癌I（AIB 1）中扩增的ER α和辅激活因子在LTLC细胞中上调3倍。VN/14-1对MCF-7 Ca细胞芳香化酶活性和细胞生长值均有抑制作用，IC_（50）分别为8.5和10.5nmol/L。在人胎盘微粒体中，芳香化酶活性受到抑制，IC_（50）为8.0 pmol/L。LTLC细胞的IC_（50）为0.83 nmol/L，与来曲唑对MCF-7 Ca细胞的IC_（50）（0.3 nmol/L）相似。LTLC细胞对VN/14-1生长抑制的敏感性是MCF-7 Ca细胞的10倍。VN/14-1处理有效地下调ER α、AIB 1、pMAPK、HER-2、细胞周期蛋白D1、细胞周期蛋白依赖性激酶4（CDK 4）和Bcl 2，并上调细胞角蛋白8/18、Bad和Bax。卵巢切除裸鼠的肿瘤生长不依赖于雌激素，但VN/ 14-1（20 mg/kg/d; P < 0.002）可抑制肿瘤生长。在肿瘤样品中，ER α、细胞周期蛋白D1、CDK 4和pMAPK的降低以及VN/14-1对细胞角蛋白、Bad和Bax的上调可能是该化合物在体外和体内抑制LTLC细胞生长的功效的原因。
Aromatase inhibitors are proving to be more effective than tamoxifen for postmenopausal estrogen receptor (ER)-positive breast cancer. However, the inevitable development of resistance to treatment is a concern. We investigated the effects of novel retinoic acid metabolism blocking agent, VN/14-1, in overcoming letrozole resistance in long-term letrozole cultured (LTLC) cells. Compared with MCF-7 cells stably transfected with aromatase (MCF-7Ca), LTLC cells were no longer sensitive to growth inhibition by aromatase inhibitors. The HER-2/phosphorylated mitogen-activated protein kinase (pMAPK) growth factor signaling pathways were activated, and ER alpha and coactivator amplified in breast cancer I (AIB1) were up-regulated similar to 3-fold in LTLC cells. VN/14-1 inhibited aromatase activity and growth values of in MCF-7Ca cells with IC50 of 8.5 and 10.5 nmol/L, respectively. In human placental microsomes, aromatase activity was inhibited with IC50 Of 8.0 pmol/L. The IC50 in LTLC cells was 0.83 nmol/L, similar to letrozole (IC50, 0.3 nmol/L) in MCF-7Ca cells. LTLC cells were 10-fold more sensitive to growth inhibition by VN/14-1 than MCF-7Ca cells. VN/14-1 treatment effectively down-regulated ER alpha, AIB1, pMAPK, HER-2, cyclin D1, cyclin-dependent kinase 4 (CDK4), and Bcl2 and up-regulated cytokeratins 8/18, Bad, and Bax. Tumor growth of LTLC cells in ovariectomized nude mice was independent of estrogens but was inhibited by VN/ 14-1 (20 mg/kg/d; P < 0.002). Decreases in ER alpha, cyclin D1, CDK4, and pMAPK and up-regulation of cytokeratins, Bad, and Bax with VN/14-1 in tumor samples may be responsible for the efficacy of this compound in inhibiting LTLC cell growth in vitro and in vivo.