Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (Key Laboratory of Biosynthesis of Natural Products, Ministry of Health of PRC and Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education of PRC), Beijing, People's Republic of China.
Cancer Chemother Pharmacol. 2010 Oct;66(5):851-9. doi: 10.1007/s00280-009-1229-9. Epub 2010 Jan 6.
To investigate the reversal mechanisms of a novel semisynthetic taxane derivative, Syl611. Syl611 is a structurally modified compound from Sinenxan A, and the chemical structure is entirely new. It was found to significantly increase paclitaxel-induced cytotoxicity in drug-resistant cells, while presenting a low level of cytotoxicity.
The in vitro cytotoxic and MDR-reversing activities of the Syl611 were determined by MTT assays. The cytotoxicity enhancement of paclitaxel was performed using the acridine orange/ethidium bromide double staining. Rhodamine 123 accumulation and retention assay in KB/V cells, Caco-2 monolayer model were used to find mechanism of action.
The cytotoxicity of Syl611 was wondrously lower in all tested cell lines than that of paclitaxel. Cytotoxicity enhancement from Syl611 was dramatically higher than that of verapamil of the same concentration (10 muM): the reversal fold index for A549/Paclitaxel, KB/V, and Bel7402/5-FU were 45.95, 73.56, and 107.13 (Syl611) and 11.36, 23.92, and 70.42 (verapamil). AO/EB double staining assay equally showed that Syl611 could enhance the cytotoxicity induced by paclitaxel. Furthermore, Syl611 could also increase the intracellular accumulation of Rhodamine 123 in KB/V cells without affecting P-gp's expression, and this accumulation was reversible. In bidirectional permeability assay, Syl611 increased the permeability of paclitaxel but decreased the net secretory of paclitaxel.
Syl611 is an effective and potential agent in reversing multidrug resistance (MDR) by multiple actions, which attributed to p-glycoprotein inhibition and drug permeability enhancement.
研究新型半合成紫杉烷衍生物 Syl611 的逆转机制。Syl611 是从 Sinenxan A 中结构修饰得到的化合物，其化学结构完全是新的。它被发现能显著增加耐药细胞中紫杉醇诱导的细胞毒性，同时表现出低水平的细胞毒性。
通过 MTT 测定法测定 Syl611 的体外细胞毒性和多药耐药逆转活性。使用吖啶橙/溴化乙锭双重染色法进行紫杉醇的细胞毒性增强实验。使用 KB/V 细胞中的罗丹明 123 积累和保留测定法以及 Caco-2 单层模型来寻找作用机制。
Syl611 的细胞毒性在所有测试的细胞系中都比紫杉醇低得多。Syl611 的细胞毒性增强作用明显高于相同浓度（10 μM）的维拉帕米：A549/Paclitaxel、KB/V 和 Bel7402/5-FU 的逆转倍数指数分别为 45.95、73.56 和 107.13（Syl611）和 11.36、23.92 和 70.42（维拉帕米）。AO/EB 双重染色实验同样表明，Syl611 可以增强紫杉醇诱导的细胞毒性。此外，Syl611 还可以增加 KB/V 细胞中 Rhodamine 123 的细胞内积累，而不影响 P-糖蛋白的表达，并且这种积累是可逆的。在双向渗透测定中，Syl611 增加了紫杉醇的通透性，但降低了紫杉醇的净分泌。
Syl611 是一种通过多种作用有效逆转多药耐药（MDR）的潜在药物，这归因于 P-糖蛋白抑制和药物通透性增强。
