Induction of mitochondria‐involved apoptosis in estrogen receptor‐negative cells by a novel tamoxifen derivative, ridaifen‐B
Induction of mitochondria‐involved apoptosis in estrogen receptor‐negative cells by a novel tamoxifen derivative, ridaifen‐B
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DOI：
10.1111/j.1349-7006.2007.00709.x
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发表时间：
2008-03
期刊：
影响因子：
5.7
通讯作者：
Y. Nagahara;Isamu Shiina;Kenya Nakata;Akane Sasaki;Tomomi Miyamoto;M. Ikekita
中科院分区：
文献类型：
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作者：
Y. Nagahara;Isamu Shiina;Kenya Nakata;Akane Sasaki;Tomomi Miyamoto;M. Ikekita
他莫昔芬是一种雌激素受体拮抗剂，广泛用作雌激素受体阳性乳腺癌药物，阻断生长信号并引发细胞凋亡。然而，最近的研究表明，他莫昔芬诱导凋亡，即使在雌激素受体阴性细胞。在本研究中，我们合成了几种他莫昔芬衍生物来增强他莫昔芬的凋亡诱导作用，并评估了凋亡诱导途径。用他莫昔芬和合成的他莫昔芬衍生物处理雌激素受体阳性人白血病细胞系HL-60和雌激素受体阴性人白血病细胞系Jurkat，然后进行细胞活力检测试验。他莫昔芬衍生物，以及先导化合物他莫昔芬，降低细胞活力，尽管表达雌激素受体。在所有合成的他莫昔芬衍生物中，ridaifen-B B具有比他莫昔芬更强的癌细胞损伤活性。日达芬B使Jurkat细胞DNA断裂并激活半胱天冬酶，表明日达芬B诱导的凋亡途径不依赖于雌激素受体。此外，线粒体参与ridaifen-B-诱导细胞凋亡的估计。Ridaifen B显著降低线粒体膜电位，Bcl-2过表达抑制Ridaifen B诱导的细胞凋亡。这些结果表明，诱导细胞凋亡的ridaifen B，一种新的他莫昔芬衍生物，是依赖于线粒体扰动没有雌激素受体参与。（Cancer Sci 2008; 99：608-614）
Tamoxifen is an antagonist of estrogen receptor, which is used widely as an estrogen receptor‐positive breast cancer drug that blocks growth signals and provokes apoptosis. However, recent studies have revealed that tamoxifen induces apoptosis even in estrogen receptor‐negative cells. In the present study, we synthesized several tamoxifen derivatives to augment the apoptosis‐inducing effect of tamoxifen and evaluated the apoptosis‐inducing pathway. The estrogen receptor‐positive human leukemia cell line HL‐60 and estrogen receptor‐negative human leukemia cell line Jurkat were treated with tamoxifen and synthesized tamoxifen derivatives, and thereafter subjected to cell viability‐detection assays. Tamoxifen derivatives, as well as the lead compound tamoxifen, decreased the cell viability despite the expression of estrogen receptor. Among all of the synthesized tamoxifen derivatives, ridaifen‐B had more potent cancer cell‐damaging activity than tamoxifen. Ridaifen‐B fragmented Jurkat cell DNA and activated caspases, suggesting that the ridaifen‐B‐induced apoptosis pathway is estrogen receptor independent. Moreover, mitochondrial involvement during ridaifen‐B‐induced apoptosis was estimated. Ridaifen‐B significantly reduced mitochondrial membrane potential, and overexpression of Bcl‐2 inhibited ridaifen‐B‐induced apoptosis. These results suggest that the induction of apoptosis by ridaifen‐B, a novel tamoxifen derivative, is dependent on mitochondrial perturbation without estrogen receptor involvement. (Cancer Sci 2008; 99: 608–614)