TiIV uptake and release by human serum transferrin and recognition of TiIV-transferrin by cancer cells:: Understanding the mechanism of action of the anticancer drug titanocene dichloride
TiIV uptake and release by human serum transferrin and recognition of TiIV-transferrin by cancer cells:: Understanding the mechanism of action of the anticancer drug titanocene dichloride
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DOI：
10.1021/bi000798z
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发表时间：
2000-08-22
期刊：
影响因子：
2.9
通讯作者：
Sadler, PJ
中科院分区：
文献类型：
--
作者：
Guo, ML;Sun, HZ;Sadler, PJ
有机金属抗癌剂二氯二茂钛，Cp 2 TiCl 2，现在作为抗癌药物处于II期临床试验中，但其作用机制知之甚少。我们在这里表明，Cp 2 TiCl 2与人血清转铁蛋白（hTF）和Ti-2-hTF与三磷酸腺苷（ATP）的相互作用具有的特性，可以允许;转铁蛋白作为介体钛输送到肿瘤细胞。因此，这些反应可能对这类新药的抗癌活性很重要。Cp 2 TiCl 2在生理条件下（100 mM NaCl、25 mM碳酸氢盐和4 mM磷酸盐，pH 7.4）与人脱辅基转铁蛋白快速反应，碳酸盐作为协同阴离子。Cp配体从药物中释放。β-[C-13]Met-hTF的二维[H-1，C-13] NMR研究表明，Ti-IV首先装载C-端，然后装载N-端，并结合在特定的Fe-III位点。Ti-IV诱导的蛋白质构象变化似乎与Fem诱导的蛋白质构象变化相似。碳酸根可在Ti-2-hTF中充当协同阴离子，但似乎不是必需的。甚至在不存在碳酸氢盐的情况下也形成特定的Ti-IV-hTF加合物。当Ti-2-hTF溶液的pH降低时，在内体pH约为2.5时没有Ti-IV释放。5.0-5.5，但一种Ti-IV在pH 4.5-2.0之间解离。相比之下，在1 mM ATP存在下，当pH从7.0降低至4.5时，所有Ti-IV都容易从两个肺叶释放。此外，Fe III从Ti-2-hTF的C-叶迅速置换Ti-IV（
The organometallic anticancer agent titanocene dichloride, Cp2TiCl2, is now in phase II clinical trials as an anticancer drug, but its mechanism of action is poorly understood. We show here that the interactions of Cp2TiCl2 with human serum transferrin (hTF) and that of Ti-2-hTF with adenosine triphosphate (ATP) have characteristics that could allow; transferrin to act as a mediator for titanium delivery to tumor cells. Such reactions may therefore be important to the anticancer activity of this new class of drugs. Cp2TiCl2 reacts rapidly with human apo-transferrin under physiological conditions (100 mM NaCl, 25 mM bicarbonate, and 4 mM phosphate, pH 7.4) with carbonate as a synergistic anion. The Cp ligands are released from the drug. Two-dimensional [H-1, C-13] NMR studies of epsilon-[C-13]Met-hTF show that Ti-IV loads the C-lobe first followed by the N-lobe and binds in the specific Fe-III sites. The protein conformational changes induced by Ti-IV appear to be similar to those induced by Fem. Carbonate can act as a synergistic anion in Ti-2-hTF but does not appear to be essential. A specific Ti-IV-hTF adduct is formed even in the absence of bicarbonate. When the pH of Ti-2-hTF solutions is lowered, no Ti-IV is released at the endosomal pH of ca. 5.0-5.5, but one Ti-IV dissociates between pH 4.5-2.0. In contrast, in the presence of 1 mM ATP, all Ti-IV is readily released from both lobes when the pH is lowered from 7.0 to 4.5. Moreover, FeIII displaces Ti-IV rapidly from the C-lobe of Ti-2-hTF (