Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
Mol Cancer. 2010 Jun 15;9:147. doi: 10.1186/1476-4598-9-147.
Cisplatin and its derivatives are commonly used anti-cancer drugs. However, cisplatin has clinical limitations including serious side effects and frequent emergence of intrinsic or acquired resistance. Thus, the novel platinum(IV) complex LA-12 represents a promising treatment modality, which shows increased intracellular penetration resulting in improved cytotoxicity in various cancer cell lines, including cisplatin resistant cells.
LA-12 disrupts cellular proliferation regardless of the p53 status in the cells, however the potency of the drug is greatly enhanced by the presence of a functional p53, indicating several mechanisms of action. Similarly to cisplatin, an interaction of LA-12 with molecular chaperone Hsp90 was proposed. Binding of LA-12 to Hsp90 was demonstrated by Hsp90 immunoprecipitation followed by platinum measurement using atomic absorption spectrometry (AAS). An inhibitory effect of LA-12 on Hsp90 chaperoning function was shown by decrease of Hsp90-assisted wild-type p53 binding to p21WAF1 promoter sequence in vitro and by accelerated ubiqutination and degradation of primarily unfolded mutant p53 proteins in cells exposed to LA-12.
To generalize our findings, LA-12 induced degradation of other Hsp90 client proteins such as Cyclin D1 and estrogen receptor was shown and proved as more efficient in comparison with cisplatin. This newly characterised molecular mechanism of action opens opportunities to design new cancer treatment strategy profitable from unique LA-12 properties, which combine DNA damaging and Hsp90 inhibitory effects.
顺铂及其衍生物是常用的抗癌药物。然而，顺铂存在临床局限性，包括严重的副作用和频繁出现的内在或获得性耐药。因此，新型铂（IV）配合物 LA-12 代表了一种很有前途的治疗方式，它显示出增加的细胞内渗透，从而提高了各种癌细胞系的细胞毒性，包括顺铂耐药细胞。
LA-12 破坏细胞增殖，而与细胞中的 p53 状态无关，但药物的效力大大增强了功能性 p53 的存在，表明了几种作用机制。与顺铂类似，LA-12 与分子伴侣 Hsp90 的相互作用也被提出。通过 Hsp90 免疫沉淀，然后使用原子吸收光谱法（AAS）测量铂，证明了 LA-12 与 Hsp90 的结合。LA-12 对 Hsp90 伴侣功能的抑制作用通过减少 Hsp90 辅助野生型 p53 与 p21WAF1 启动子序列的结合来证明，通过加速未折叠突变型 p53 蛋白在暴露于 LA-12 的细胞中的泛素化和降解来证明。
为了推广我们的发现，证明并证明 LA-12 诱导其他 Hsp90 客户蛋白如细胞周期蛋白 D1 和雌激素受体的降解，与顺铂相比，其效率更高。这种新表征的作用机制为设计新的癌症治疗策略提供了机会，这些策略从 LA-12 的独特特性中获益，这些特性结合了 DNA 损伤和 Hsp90 抑制作用。
