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


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.
Zhang
Yi
Y
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.
Li
Hongyan
H
Wang
Hongbo
H
Su
Fuqin
F
Qu
Runjiang
R
Yin
Dali
D
Dai
Jungui
J
Li
Yan
Y
Chen
Xiaoguang
X
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007624:KB Cells; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D010539:Permeability; D020112:Rhodamine 123 / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; C551924:Syl611 compound; D043823:Taxoids; D020112:Rhodamine 123; D014700:Verapamil; D017239:Paclitaxel