Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy.
Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy.
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含铂化合物吡啶硫酮在癌症治疗中比顺铂更强、更安全
DOI：
10.1016/j.bcp.2016.06.019
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发表时间：
2016-09-15
影响因子：
5.8
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Zhao C;Chen X;Zang D;Lan X;Liao S;Yang C;Zhang P;Wu J;Li X;Liu N;Liao Y;Huang H;Shi X;Jiang L;Liu X;He Z;Wang X;Liu J
DNA是目前铂类抗癌药物的众所周知的分子靶点;因此，它们的临床使用受到其源自非选择性DNA损伤的全身毒性和耐药性的严重限制。已经开发了各种策略来规避基于铂的化疗的缺点，但固有的问题仍然没有解决。在这里，我们报告，铂吡啶（PtPT），一种化学性质良好的铂合成复合物，抑制蛋白酶体功能，从而表现出更大的和更有选择性的细胞毒性，多种癌细胞比顺铂，没有表现出明显的DNA损伤在体外和体内。此外，与通过阻断20 S蛋白酶体的肽酶活性来抑制蛋白酶体的经典蛋白酶体抑制剂硼替佐米/万珂不同，PtPT主要使26 S蛋白酶体相关的去泛素化酶USP 14和UCHL 5失活。此外，PtPT可以选择性地诱导白血病患者的癌细胞的细胞毒性和蛋白酶体抑制，但不能诱导健康人的外周血单核细胞。在裸鼠中，PtPT也显著抑制肿瘤异种移植物的生长，而没有显示出由顺铂诱导的副作用。因此，我们发现了一种新的基于铂的抗肿瘤药物PtPT，其靶向细胞中的26 S蛋白酶体相关的去泛素化酶而不是DNA，从而发挥更安全和更有效的抗肿瘤作用，确定了一种高度可翻译的新的基于铂的抗癌策略。
DNA is the well-known molecular target of current platinum-based anticancer drugs; consequently, their clinical use is severely restricted by their systemic toxicities and drug resistance originating from non-selective DNA damage. Various strategies have been developed to circumvent the shortcomings of platinum-based chemotherapy but the inherent problem remains unsolved. Here we report that platinum pyrithione (PtPT), a chemically well-characterized synthetic complex of platinum, inhibits proteasome function and thereby exhibits greater and more selective cytotoxicity to multiple cancer cells than cisplatin, without showing discernible DNA damage both in vitro and in vivo. Moreover, unlike the classical proteasome inhibitor bortezomib/Velcade which inhibits the proteasome via blocking the peptidase activity of 20S proteasomes, PtPT primarily deactivates 26S proteasome-associated deubiquitinases USP14 and UCHL5. Furthermore, PtPT can selectively induce cytotoxicity and proteasome inhibition in cancer cells from leukemia patients but not peripheral blood mononuclear cells from healthy humans. In nude mice, PtPT also remarkably inhibited tumor xenograft growth, without showing the adverse effects that were induced by cisplatin. Hence, we have discovered a new platinum-based anti-tumor agent PtPT which targets 26S proteasome-associated deubiquitinases rather than DNA in the cell and thereby exerts safer and more potent anti-tumor effects, identifying a highly translatable new platinum-based anti-cancer strategy.