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首页> 外文期刊>Biochemistry >Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV)-transferrin by cancer cells: understanding the mechanism of action of the anticancer drug titanocene dichloride.
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Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV)-transferrin by cancer cells: understanding the mechanism of action of the anticancer drug titanocene dichloride.

机译：人类血清转铁蛋白对Ti（IV）的吸收和释放以及癌细胞对Ti（IV）-转铁蛋白的识别：了解抗癌药物二茂钛二氯化钛的作用机理。

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摘要

The organometallic anticancer agent titanocene dichloride, Cp(2)TiCl(2), 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 Cp(2)TiCl(2) 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. Cp(2)TiCl(2) 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 [(1)H, (13)C] NMR studies of epsilon-[(13)C]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 Fe(III). 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, Fe(III) displaces Ti(IV) rapidly from the C-lobe of Ti(2)-hTF (<5 min) but only slowly (days) from the N-lobe. Thus, the species Fe(C)Ti(N)-hTF might also provide a route for Ti(IV) entry into tumor cells via the transferrin receptor. Ti(2)-hTF effectively blocked cell uptake of radiolabeled (59)Fe-hTF into BeWo cells, a human placental choriocarcinoma cell line in culture. These results imply that titanium transferrin might be recognized by the transferrin receptor and be taken up into cancer cells.
机译：有机金属抗癌药二茂钛二氯化碳Cp（2）TiCl（2）现在处于II期临床试验中，作为抗癌药，但对其作用机理了解甚少。我们在这里显示，Cp（2）TiCl（2）与人血清转铁蛋白（hTF）的相互作用以及Ti（2）-hTF与三磷酸腺苷（ATP）的相互作用具有可使转铁蛋白充当钛介体的特性递送至肿瘤细胞。因此，这种反应对于这种新型药物的抗癌活性可能很重要。 Cp（2）TiCl（2）在生理条件（100 mM NaCl，25 mM碳酸氢盐和4 mM磷酸盐，pH 7.4）下与人脱铁运铁蛋白快速反应，其中碳酸根为协同阴离子。 Cp配体从药物中释放出来。 ε-[[13] C] Met-hTF的二维[（1）H，（13）C] NMR研究表明，Ti（IV）首先加载C瓣，然后是N瓣并结合在特定的Fe（III）位点。 Ti（IV）诱导的蛋白质构象变化似乎与Fe（III）诱导的相似。碳酸根可作为Ti（2）-hTF中的协同阴离子，但似乎不是必需的。即使没有碳酸氢盐，也会形成特定的Ti（IV）-hTF加合物。当Ti（2）-hTF溶液的pH值降低时，在约60的内体pH值下不会释放出Ti（IV）。 5.0-5.5，但一种Ti（IV）在pH 4.5-2.0之间解离。相反，在1 mM ATP的存在下，当pH从7.0降低到4.5时，所有Ti（IV）都容易从两个叶中释放出来。此外，Fe（III）从Ti（2）-hTF的C瓣快速移出Ti（IV）（<5分钟），但从N瓣移出缓慢（几天）。因此，Fe（C）Ti（N）-hTF物种也可能提供Ti（IV）通过运铁蛋白受体进入肿瘤细胞的途径。 Ti（2）-hTF有效地阻止了放射性标记的（59）Fe-hTF进入BeWo细胞的细胞摄取，BeWo细胞是人胎盘绒毛膜癌细胞的培养细胞。这些结果表明，转铁蛋白钛可能被转铁蛋白受体识别并被癌细胞吸收。

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