Multifunctional Pt(iv) complexes containing a glutathione S-transferase inhibitor lead to enhancing anticancer activity and preventing metastasis of osteosarcoma cells.
Multifunctional Pt(iv) complexes containing a glutathione S-transferase inhibitor lead to enhancing anticancer activity and preventing metastasis of osteosarcoma cells.
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DOI：
10.1039/c8mt00296g
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发表时间：
2019-02
期刊：
影响因子：
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通讯作者：
Hong Chen;Feihong Chen;Xinyi Wang;S. Gou
中科院分区：
文献类型：
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作者：
Hong Chen;Feihong Chen;Xinyi Wang;S. Gou
顺铂已在临床上用于骨肉瘤（OS）的治疗，但其疗效因耐药性和转移而受到严重限制。主要原因之一是癌细胞中谷胱甘肽S - 转移酶（GSTs）的过表达，这会加速谷胱甘肽（GSH）与顺铂的相互作用，降低顺铂的生物学效应。在本研究中，设计并合成了三种由顺铂与一种GST抑制剂（NBDHEX）共轭衍生的铂（IV）配合物。对这些配合物的稳定性、释放能力、抑制GSTs的能力以及它们对骨肉瘤细胞的体外抗癌活性进行了研究。其中，配合物2在轴向位置带有一个NBDHEX衍生物和一个羟基，由于其合适的稳定性和显著的抑制GSTs的能力，能够显著杀死人骨肉瘤细胞。同时，它可以通过下调Akt来预防骨肉瘤的转移。因此，配合物2具有进一步研究用于治疗骨肉瘤的潜力。
Cisplatin has been clinically applied in the treatment of osteosarcoma (OS), but its efficacy is severely limited due to drug resistance and metastasis. One of the chief culprits is the overexpression of glutathione S-transferases (GSTs) in cancer cells, which can accelerate the interaction of glutathione (GSH) with cisplatin, reducing its biological effects. In this study, three Pt(iv) complexes derived from cisplatin conjugated with a GST inhibitor (NBDHEX) were designed and synthesized. The stabilities and releasing capabilities of these complexes, as well as their abilities to inhibit GSTs, were investigated together with their in vitro anticancer activities toward osteosarcoma cells. Among them, complex 2, bearing one NBDHEX derivative and a hydroxyl group at the axial positions, could markedly kill human OS cells due to its suitable stability and prominent ability to inhibit GSTs. Meanwhile, it can prevent the metastasis of OS via down-regulating Akt. Thus, complex 2 has the potential for further research for the treatment of OS.