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首页> 外文期刊>Biochemical Pharmacology >Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: A comparative study of uptake, cell cycle and damage to cellular compartments.
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Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: A comparative study of uptake, cell cycle and damage to cellular compartments.

机译：康他汀A4类似查尔酮及其Pt配合物对癌细胞的影响：对摄取，细胞周期和对细胞区室的损害的比较研究。

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摘要

The combretastatin A4 analogous chalcone (2E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 1 and its dichloridoplatinum(II) (6-aminomethylnicotinate) complex 2 were previously found to be highly active against a variety of cancer cell lines while differing in their apoptosis induction and long-term regrowth retardation (Schobert et al. [1]). Further differences were identified now. The cellular uptake of complex 2, like that of oxaliplatin, occurred mainly via organic cation transporters (OCT-1/2; approximately 32%) and copper transporter related proteins (Ctr1; approximately 24%), whereas that of chalcone 1 was dependent on endocytosis ( approximately 80%). Complex 2 was more tumour-specific than 1 concerning neural cells. This was apparent from the ratios of IC(50)(48h) values against primary astrocytes versus human glioma cells U87 (>7000 for complex 2; 55 for compound 1). In tubulin-rich neurons and 518A2 melanoma cells complex 2 disrupted microtubules and actin filaments. Cancer cells treated with 2 could repair the cytoskeletal damage but ceased to proliferate and perished. Complex 2 was particularly cytotoxic against P-gp-rich cells. It acted as a substrate for ABC-transporters of types BCRP, MRP3, and MRP1 and so was less active against the corresponding cancer cell lines. Complex 2 arrested the cell cycle of the melanoma cells in G(1) and G(2)/M phases. A fragmentation of their Golgi apparatus was observed by TEM for incubation with complex 2 but not with 1. In conclusion, unlike chalcone 1, its platinum complex 2 is highly cell line specific, is taken up via cell-controlled transporters and induces apoptosis by triggering multiple targets.
机译：康他汀A4类似查尔酮（2E）-3-（3-羟基-4-甲氧基苯基）-1-（3,4,5-三甲氧基苯基）丙-2-烯-1-酮1及其二氯铂（II）（6先前发现，β-氨基甲基烟酸酯复合物2对多种癌细胞具有高活性，而它们在凋亡诱导和长期再生迟缓方面有所不同（Schobert等人[1]）。现在发现了进一步的差异。复合物2的细胞摄取与奥沙利铂一样，主要通过有机阳离子转运蛋白（OCT-1 / 2;约32％）和铜转运蛋白相关蛋白（Ctr1;约24％）发生，而查尔酮1依赖于胞吞作用（约80％）。关于神经细胞，复合物2的肿瘤特异性高于1。从针对原代星形胶质细胞与人神经胶质瘤细胞U87的IC（50）（48h）值之比（复合物2> 7000;化合物1 55）的比例显而易见。在富含微管蛋白的神经元和518A2黑色素瘤细胞中，复合物2破坏了微管和肌动蛋白丝。用2处理的癌细胞可以修复细胞骨架损伤，但不再增殖和消失。复合物2对富含P-gp的细胞具有特别的细胞毒性。它充当BCRP，MRP3和MRP1类型的ABC转运蛋白的底物，因此对相应的癌细胞系活性较低。复合物2逮捕了G（1）和G（2）/ M期的黑色素瘤细胞的细胞周期。透射电镜观察到它们与复合物2一起孵育而不是与1一起孵育，其高尔基体破碎了。总之，与查尔酮1不同，其铂复合物2具有高度的细胞系特异性，可通过细胞控制的转运蛋白摄取，并通过触发而诱导凋亡多个目标。

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