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Syl611, a novel semisynthetic taxane derivative, reverses multidrug resistance by p-glycoprotein inhibition and facilitating inward transmembrane action

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Abstract

Purpose

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.

Methods

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.

Results

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 μM): 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.

Conclusions

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.

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Acknowledgments

We thank Dr. Xuguang Zheng and Christopher Shih for critical reading of this paper. This study was supported by the National Natural Science Key Foundation (Grant No.30630069)

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Authors and Affiliations

  1. 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), 1 Xian Nong Tan Street, 100050, Beijing, People’s Republic of China

    Yi Zhang, Hongyan Li, Hongbo Wang, Fuqin Su, Runjiang Qu, Yan Li & Xiaoguang Chen

  2. Department of Medicinal Chemistry, 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), 1 Xian Nong Tan Street, 100050, Beijing, People’s Republic of China

    Dali Yin

  3. Department of Biosynthesis of Natural Products, 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), 1 Xian Nong Tan Street, 100050, Beijing, People’s Republic of China

    Jungui Dai

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  1. Yi Zhang
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  2. Hongyan Li
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  3. Hongbo Wang
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  7. Jungui Dai
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  8. Yan Li
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  9. Xiaoguang Chen
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Correspondence to Xiaoguang Chen.

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Zhang, Y., Li, H., Wang, H. et al. Syl611, a novel semisynthetic taxane derivative, reverses multidrug resistance by p-glycoprotein inhibition and facilitating inward transmembrane action. Cancer Chemother Pharmacol 66, 851–859 (2010). https://doi.org/10.1007/s00280-009-1229-9

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  • DOI: https://doi.org/10.1007/s00280-009-1229-9

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