4-(4-Pyridinyl methylene) curcumin (C1206) is a new derivative of curcumin that is more active than curcumin in inhibition of heat shock protein 90 (Hsp90) and antitumor action. In this study we investigated the relationship between C1206-induced inhibition of Hsp90 and its anti-leukemic effects. The fluorescence quenching experiments showed that C1206 seemed to bind the middle dimerization domain of Hsp90. The interaction between C1206 and Hsp90 was driven mainly by electrostatic interaction. In in vitro enzyme activity assay, C1206 dose-dependently inhibited Hsp90 ATPase activity with an IC₅₀ value of 4.17 μmol/L. In both imatinib-sensitive K562 chronic myeloid leukemia cells and imatinib-resistant K562/G₀₁ chronic myeloid leukemia cells, C1206 (0.4-3.2 μmol/L) dose-dependently caused the degradation of Hsp90 client proteins and downstream proteins (AKT, MEK, ERK, C-RAF, P-AKT, P-MEK and P-ERK). Furthermore, C1206 (0.4-3.2 μmol/L) dose-dependently induced apoptosis of K562 and K562/G₀₁ cells through triggering mitochondrial pathway. Consistent with this result, C1206 inhibited the proliferation of K562 and K562/G₀₁ cells with IC₅₀ values of 1.10 and 0.60 μmol/L, respectively. These results suggest that C1206 is a novel Hsp90 inhibitor and a promising therapeutic agent for chronic myeloid leukemia.

中文翻译：

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C1206是一种新型姜黄素衍生物，可在体外有效抑制Hsp90和人类慢性粒细胞白血病细胞。

4-（4-吡啶基亚甲基）姜黄素（C1206）是姜黄素的新衍生物，在抑制热休克蛋白90（Hsp90）和抗肿瘤作用方面比姜黄素更具活性。在这项研究中，我们研究了C1206诱导的Hsp90抑制与其抗白血病作用之间的关系。荧光猝灭实验表明，C1206似乎结合了Hsp90的中间二聚结构域。C1206和Hsp90之间的相互作用主要由静电相互作用驱动。在体外酶活性测定中，C1206剂量依赖性地抑制Hsp90 ATPase活性，IC ₅₀值为4.17μmol / L。在对伊马替尼敏感的K562慢性髓细胞白血病细胞和对伊马替尼耐药的K562 / G _01中慢性髓样白血病细胞C1206（0.4-3.2μmol/ L）剂量依赖性地引起Hsp90客户蛋白和下游蛋白（AKT，MEK，ERK，C-RAF，P-AKT，P-MEK和P-ERK）的降解。此外，C1206（0.4-3.2μmol/ L）通过触发线粒体途径剂量依赖性地诱导K562和K562 / G ₀₁细胞凋亡。与此结果一致，C1206抑制K562和K562 / G ₀₁细胞的增殖，其IC ₅₀值分别为1.10和0.60μmol/ L。这些结果表明，C1206是一种新型的Hsp90抑制剂，也是治疗慢性粒细胞白血病的有希望的治疗剂。