Buschini Annamaria, Pinelli Silvana, Alinovi Rossella, Mussi Francesca, Bisceglie Franco, Rivetti Claudio, Doniselli Nicola, Pelosi Giorgio
Dipartimento di Bioscienze, Università di Parma, Parco Area delle Scienze 11A, 43124 Parma, Italy.
Metallomics. 2014 Apr;6(4):783-92. doi: 10.1039/c3mt00345k.
Bis(S-citronellalthiosemicarbazonato)nickel(II), [Ni(tcitr)2], is a compound that inhibits proliferation of tumour line U937 by inducing a G2/M block and leading the cancer cells to apoptosis. This nickel derivative shows no activity on non proliferating healthy cells. In this paper we report our studies on the action mechanisms of [Ni(tcitr)2]. Apoptosis in U937 cells exposed to [Ni(tcitr)2] takes place through activation of caspase-9, and therefore through an intrinsic triggering mechanism. Given the DNA damage observed in the Comet assay, the mutagenic activity of the metal complex was tested, including with the Ames test, micronuclei and DNA damage recovery, but neither mutagenicity nor recovery were detected. Nickel-complex-DNA interactions were analyzed by direct action of the compound on plasmidic and linear DNA by UV-vis and CD spectroscopy, gel electrophoresis and Atomic Force Microscopy. These experiments reveal that [Ni(tcitr)2] does not cause DNA breaks and does not intercalate, but significantly alters the DNA conformation creating knot-like structures and hairpins.
双（S-香茅醛缩氨基硫脲）镍（II），即[Ni(tcitr)₂]，是一种通过诱导G2/M期阻滞并导致癌细胞凋亡来抑制肿瘤细胞系U937增殖的化合物。这种镍衍生物对非增殖性健康细胞无活性。在本文中，我们报告了对[Ni(tcitr)₂]作用机制的研究。暴露于[Ni(tcitr)₂]的U937细胞中的凋亡通过激活半胱天冬酶-9发生，因此是通过一种内在触发机制。鉴于彗星试验中观察到的DNA损伤，对金属配合物的诱变活性进行了测试，包括艾姆斯试验、微核试验和DNA损伤恢复试验，但未检测到诱变活性和恢复情况。通过紫外可见光谱和圆二色光谱、凝胶电泳和原子力显微镜对化合物与质粒DNA和线性DNA的直接作用来分析镍配合物与DNA的相互作用。这些实验表明，[Ni(tcitr)₂]不会导致DNA断裂且不会嵌入，但会显著改变DNA构象，形成结状结构和发夹结构。
