Enhanced cytotoxicity of nitidine against camptothecin-resistant A549 cells

Abstract

Aim Drug resistance has been a major issue in cancer chemotherapy. It is therefore important to screen more potent natural anti-cancer agents for use against the drug-resistant cancer phenotype. The present study investigated the cytotoxicity of the traditional and natural medicinal agent nitidine (NTD) against the drug-resistant cancer phenotype of A549 human lung adenocarcinoma cells. Methods The camptothecin (CPT) tolerant phenotype was selected after A549 cells were exposed to CPT for 1 week. The cytotoxicity of NTD in these CPT-resistant cells (CRC) was studied in vitro in relation to its accumulation and expression of the ATP binding cassette (ABC) transporter gene. Results CRC expressing higher levels of ABCC1, ABCC2, ABCC3, and ABCA1 were more resistant to CPT compared with normal A549 cells. CRC were, however, more susceptible to NTD compared with normal A549 cells with preferential accumulation of NTD. A statistically significant difference in protein level between normal A549 and CRC was noted only for ABCC1 and ABCC2. Furthermore, gene expression of ABCC2 and ABCC3 had a positive correlation with NTD accumulation, and negative correlation with the effective dose that inhibited 50% of cell growth (D50) of this agent in nine cancer cell panels. Conclusion CRC were found to be more susceptible to NTD compared with the normal phenotype. The cytotoxicity of NTD was associated with its accumulation and the expression of ABCC2, suggesting the involvement of this transporter in the selective incorporation of NTD into cancer cells, resulting in enhanced cytotoxicity.