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  • Title: The establishment of two paclitaxel-resistant prostate cancer cell lines and the mechanisms of paclitaxel resistance with two cell lines.
    Author: Takeda M, Mizokami A, Mamiya K, Li YQ, Zhang J, Keller ET, Namiki M.
    Journal: Prostate; 2007 Jun 15; 67(9):955-67. PubMed ID: 17440963.
    Abstract:
    BACKGROUND: Although paclitaxel is used for hormone-resistant prostate cancer, relapse definitely occurs later. Details of the molecular mechanism responsible for paclitaxel- resistance remain unclear. METHODS: We established paclitaxel-resistant cells, DU145-TxR and PC-3-TxR from parent DU145 and PC-3. To characterize these cells, we examined cross-resistance to other anticancer drugs. Expression of several potential genes that had been related to drug-resistance was compared with parent cells by RT-PCR and Western blotting. Methylation analysis of multiple drug resistance (MDR1) promoter was carried out using bisulfite-modified DNA from cell lines. Knockdown experiments using small interfering RNA (siRNA) were also performed to confirm responsibility of drug-resistance. Finally, cDNA microarray was performed to quantify gene expression in PC-3 and PC-3-TxR cells. RESULTS: The IC(50) for paclitaxel in DU145-TxR and PC-3-TxR was 34.0- and 43.4-fold higher than that in both parent cells, respectively. Both cells showed cross-resistance to some drugs, but not to VP-16 and cisplatin. Methylation analysis revealed that methylated CpG sites of MDR1 promoter in DU145 and PC-3 cells were demethylated in DU145-TxR cells, but not in PC-3-TxR cells. Knockdown of P-glycoprotein (P-gp), which was up-regulated in resistant cells, by MDR-1 siRNA restored paclitaxel sensitivity in DU145-TxR but not in PC-3-TxR, indicating that up-regulation of P-gp was not always main cause of paclitaxel-resistance. Microarray analysis identified 201 (1.34%) up-regulated genes and 218 (1.45%) out of screened genes in PC-3-TxR. CONCLUSIONS: Our data will provide molecular mechanisms of paclitaxel-resistance and be useful for screening target genes to diagnose paclitaxel sensitivity.
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