A study on platinum(iv) species containing an estrogen receptor modulator to reverse tamoxifen resistance of breast cancer†,Metallomics

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A study on platinum(iv) species containing an estrogen receptor modulator to reverse tamoxifen resistance of breast cancer†
Metallomics ( IF 2.9 ) Pub Date : 2017-12-19 00:00:00 , DOI: 10.1039/c7mt00289k
Weiwei Hu _{1,

2,

3,

4,

5} , Jian Zhao _{1,

2,

3,

4,

5} , Wuyang Hua _{1,

2,

3,

4} , Shaohua Gou _{1,

2,

3,

4,

5}

Affiliation

Several dual-action Tam–Pt(IV) complexes derived from tamoxifen (Tam) and platinum(II) drugs were designed and synthesized for targeting estrogen receptors (ERs) and DNA. These novel compounds not only exhibited potent cytotoxicity against breast cancer cells, but also reversed the tamoxifen resistance of TamR-MCF-7 cancer cells. Computational docking assays together with cellular uptake data demonstrated that the ER ligand portion of these conjugates plays a targeting role in ER-positive tumor cells and promotes the uptake of platinum via an estrogen receptor-mediated pathway. A study on the preliminary mechanism of the typical conjugate, complex 1, revealed that the Tam–Pt(IV) complex induced apoptosis via the mitochondrial-dependent apoptosis pathway mediated through the activation of caspase 3 and PARP proteins. These results suggested that the conjugation of estrogen receptor modulators with the platinum moiety could facilitate a selective enrichment of platinum in estrogen-positive tumors and possibly broaden the scope of ER ligand clinical use to resistant breast tumors.

中文翻译：

含有雌激素受体调节剂以逆转乳腺癌的他莫昔芬耐药性的铂（iv）物种的研究†

设计并合成了几种针对他莫昔芬（Tam）和铂（II）药物的双作用Tam–Pt（IV）复合物，以靶向雌激素受体（ERs）和DNA。这些新颖的化合物不仅对乳腺癌细胞表现出强力的细胞毒性，而且还逆转了TamR-MCF-7癌细胞对他莫昔芬的耐药性。计算对接分析与细胞摄取数据一起证明，这些结合物的ER配体部分在ER阳性肿瘤细胞中起靶向作用，并通过雌激素受体介导的途径促进铂的摄取。对典型的缀合物1的初步机理的研究表明，Tam–Pt（IV）复合物可诱导细胞凋亡通过激活caspase 3和PARP蛋白介导的线粒体依赖性细胞凋亡途径。这些结果表明，雌激素受体调节剂与铂部分的缀合可以促进铂在雌激素阳性肿瘤中的选择性富集，并可能扩大ER配体在抗药性乳腺肿瘤中的临床应用范围。

更新日期：2017-12-19

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