演題抄録

International Session(Poster)

開催概要
開催回
第51回・2013年・京都
 

Combined therapy in Paclitaxel-resistance: manipulation of MDR and Nrf2/GR Axis

演題番号 : ISP-4

[筆頭演者]
Ching-Chuan Kuo:1 
[共同演者]
Huang-Hui Chen:1、Yen-Wen Huang:1、Jang-Yang Chang:2、Yun-Ning Yang:1、Jin-Fen Liu:2

1:Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taiwan、2:National Institute of Cancer Research, National Health Research Institutes, Taiwan

 

Paclitaxel-based regimen is the front-line treatment of oral cancer; however, drug resistance is frequently encountered in the clinic. Despite activation of P-gp170/MDR-mediated drug efflux is a main problem for paclitaxel resistance, inhibition of P-gp170/MDR function could not completely restore drug sensitivity. Other mechanisms for paclitaxel resistance in oral cancer merit further investigation. Two paclitaxel-resistant sublines (KB-S5 and KB-S15) derived from KB cells were obtained. Cell viability assay, qRT-PCR, Western blot, immunofluorescence staining, antioxidant-related activity determination, and siRNA interference were applied. In this study, KB-S5 and KB-S15 cells showed upon 10-fold resistance to paclitaxel as compared to parental KB cells. These two paclitaxel-resistant clones displayed a classical P-gp170/MDR-mediated drug resistance phenotype. However, inhibition of P-gp170/MDR functions by verapamil partial reversed paclitaxel resistance. In the present study, we found that activation of a redox-sensitive transcriptional factor, Nrf2, with increased expression of ARE-dependent gene, glutathione reductase (GR), leads to increase the total antioxidant capacity (TAC) in KB-S5 and KB-S15. Silencing of Nrf2 or GR by RNA interference further confirmed that Nrf2/GR axis contributes to increase TAC followed by development of paclitaxel resistance in these cells. Notably, co-inhibition of P-gp170/MDR and Nrf2/GR axis by verapemil and Nrf2/GR targeted siRNA completely restored paclitaxel efficacy in KB-S5 and KB-S15 cells as compared to parental cells. Taken together, we demonstrated for the first time that activation of Nrf2/GR axis contributes paclitaxel-mediated drug resistance. Discovery of a therapeutic strategy by co-manipulation of P-gp170/MDR and Nrf2/GR axis is worth for treating refractory oral malignancies.

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