Multidrug resistance-associated protein 3 and Bcl-2 contribute to multidrug resistance by vinorelbine in lung adenocarcinoma.

ABSTRACT

Although cancer cells initially respond to vinorelbine (NVB), the acquisition of resistance to the treatment is the main cause of chemotherapeutic failure in lung cancer. The intrinsic mechanism of drug resistance induced by NVB in lung cancer is not clear and tumor cell models to study NVB resistance have not been widely studied. We previously established a NVB resistant cell line, Anip973/NVB, derived from the Anip973 lung adenocarcinoma cell line. The aim of this study was to investigate the molecular mechanisms involved in the resistance to NVB in lung adenocarcinoma. Genetic profiles of Anip973/NVB and Anip973 cells were compared by microarray analysis and qRT-PCR. Tumor xenografts were obtained by grafting Anip973/NVB and Anip973 cells into nude mice and the xenograft response to NVB or control treatment was evaluated. Morphological assessment of xenograft tissues was performed by transmission electron microscopy (TEM). Immunohistochemistry (IHC) was used to compare Bcl-2 and MRP3 protein expression in xenografts. Fifty-five up-regulated genes and 88 down-regulated genes in Anip973/NVB cells compared with Anip973 cells were identified by cDNA microarray analysis. Up-regulation of MRP3 and Bcl-2 was confirmed by qRT-PCR. NVB inhibits xenografts of Anip973 growth but did not affect xenografts of Anip973/NVB growth. Ultrastructural changes observed by TEM showed that NVB induces apoptosis in the Anip973-treated group but not in the Anip973/NVB-treated group. Higher expression rates of Bcl-2 and MRP3 were observed in Anip973/NVB xenograft cells compared with Anip973 xenograft cells by IHC. In conclusion, in the present study, we identified a set of genes responsible for multidrug resistance in Anip973/NVB cells. Among them, MRP3 and Bcl-2 may participate in lung adenocarcinoma multidrug resistance induced by NVB.