Cholesterol biosynthesis inhibitors as potent novel anti-cancer agents: suppression of hormone-dependent breast cancer by the oxidosqualene cyclase inhibitor RO 48-8071
Cholesterol biosynthesis inhibitors as potent novel anti-cancer agents: suppression of hormone-dependent breast cancer by the oxidosqualene cyclase inhibitor RO 48-8071
复制标题
DOI：
10.1007/s10549-014-2996-5
复制
发表时间：
2014-07-01
影响因子：
3.8
通讯作者：
Hyder, Salman M.
中科院分区：
文献类型：
--
作者：
Liang, Yayun;Besch-Williford, Cynthia;Hyder, Salman M.
在大多数人类乳腺癌中，肿瘤细胞增殖依赖于雌激素。尽管激素反应性肿瘤最初对抗雌激素治疗有反应，但大多数最终会产生耐药性。我们的目标是确定可以调节以控制乳腺癌进展的替代靶点。 Sulforhodamine B 测定用于测量暴露于各种抑制剂的培养的人乳腺癌细胞系的活力。通过蛋白质印迹法测定全细胞提取物中的蛋白质表达。 BT-474裸鼠肿瘤异种移植物用于肿瘤进展的体内研究。 RO 48-8071（[4'-[6-（烯丙基甲基氨基）己氧基]-4-溴-2'-氟二苯甲酮富马酸酯]；RO）是一种氧化角鲨烯环化酶（OSC，胆固醇生物合成中的关键酶）的小分子抑制剂，可有效降低乳腺癌细胞活力。雌激素受体 (ER) 阳性人乳腺癌细胞在体外暴露于药理学水平的 RO 或接近 OSC (nM) IC50 的剂量会降低细胞活力。对带有 BT-474 肿瘤异种移植物的小鼠施用 RO 可阻止肿瘤生长，且无明显毒性。 RO 降解 ER α，同时诱导抗增殖蛋白 ER β。另外两种降胆固醇药物氟伐他汀和辛伐他汀在降低乳腺癌细胞活力方面效果较差，并且被发现不会诱导 ER β。 ER beta 抑制或敲低可防止 RO 依赖性细胞活力丧失。重要的是，RO 对正常人乳腺细胞的活力没有影响。 RO 是激素依赖性人类乳腺癌细胞增殖的有效抑制剂。 RO 的抗肿瘤特性似乎部分是由于脱靶效应增加了乳腺癌细胞中 ER β/ER α 的比例。
In most human breast cancers, tumor cell proliferation is estrogen dependent. Although hormone-responsive tumors initially respond to anti-estrogen therapies, most of them eventually develop resistance. Our goal was to identify alternative targets that might be regulated to control breast cancer progression. Sulforhodamine B assay was used to measure the viability of cultured human breast cancer cell lines exposed to various inhibitors. Protein expression in whole-cell extracts was determined by Western blotting. BT-474 tumor xenografts in nude mice were used for in vivo studies of tumor progression. RO 48-8071 ([4'-[6-(Allylmethylamino)hexyloxy]-4-bromo-2'-fluorobenzophenone fumarate]; RO), a small-molecule inhibitor of oxidosqualene cyclase (OSC, a key enzyme in cholesterol biosynthesis), potently reduced breast cancer cell viability. In vitro exposure of estrogen receptor (ER)-positive human breast cancer cells to pharmacological levels of RO or a dose close to the IC50 for OSC (nM) reduced cell viability. Administration of RO to mice with BT-474 tumor xenografts prevented tumor growth, with no apparent toxicity. RO degraded ER alpha while concomitantly inducing the anti-proliferative protein ER beta. Two other cholesterol-lowering drugs, Fluvastatin and Simvastatin, were less effective in reducing breast cancer cell viability and were found not to induce ER beta. ER beta inhibition or knockdown prevented RO-dependent loss of cell viability. Importantly, RO had no effect on the viability of normal human mammary cells. RO is a potent inhibitor of hormone-dependent human breast cancer cell proliferation. The anti-tumor properties of RO appear to be in part due to an off-target effect that increases the ratio of ER beta/ER alpha in breast cancer cells.