Reversal of taxol resistance by cisplatin in nasopharyngeal carcinoma by upregulating thromspondin-1 expression

Abstract

Drug resistance often causes failure of chemotherapy in nasopharyngeal carcinoma (NPC). Thus, it is of great importance to overcome drug resistance by developing effective reversal therapies. The purposes of this study were to examine whether cisplatin could reverse the taxol-resistant phenotype of NPC cells, and to evaluate the role of the taxol-resistant gene (TXR1)/thrombospondin (TSP1) pathway in the reversal of taxol resistance. A drug (taxol)-resistant cell line, CNE-1/taxol, was established from a human NPC cell line, CNE-1. The sensitivity of both CNE-1 and CNE-1/taxol to cisplatin or paclitaxel was detected using the colony formation assay. Apoptotic death was measured by flow cytometry. The expression of the TXR1 and TSP1 was determined by RT-PCR and western blot. The growth inhibition rate in CNE-1/taxol cells in response to taxol was significantly increased when they were pre-treated with low-dose cisplatin. CNE-1/taxol cells were more sensitive to cisplatin than CNE-1 cells when exposed to 300-1500 nmol/l of cisplatin. An approximate seven-fold increase in TXR1 mRNA expression and an 8.9-fold decrease in TSP1 mRNA expression were observed in taxol-resistant cells compared with their parental cells. An 8.7-fold increase in TSP1 mRNA expression was observed in CNE-1/taxol cells exposed to 590 nmol/l of cisplatin for 24 h. An increase in TSP1 protein expression was obtained in a dose-dependent manner after CNE-1/taxol cells were exposed to cisplatin. However, there was no change in TXR1 mRNA expression after both CNE-1 and CNE-1/taxol cells were exposed to cisplatin. We conclude that cisplatin reverses drug resistance through the upregulation of TSP1 downstream of TXR1.