Molecular Determinants of Response of Tumor Cells to Berberine

摘要

Berberine, an alkaloid of Hydratis canadensis (Goldenseal), reveals profound cytotoxic activity against tumor cells. The inhibition concentration 50% (IC_(50)) values for berberine of 60 cell lines of the National Cancer Institute (NCI) were correlated with those of 43,177 compounds included into the NCI database by COMPARE analysis. Among the standard cytostatic drugs, the IC_(50) values for berberine correlated significantly with those for daunorubicin, vinblastine, and paclitaxel but not with those for platinum compounds (cisplatin, carboplatin), alkylating agents (melphalan, ifosfamide), DNA topoisomerase I inhibitors (camptothecin, topothecan), and antimetabolites (5-fluorouracil, methotrexate). Significant correlations were also found to phyllanthoside, dactinomycin, didemnin B, bisantrene, maytansine, rhizoxin, geldanamycin, tetrocarcin A, and chromomycin A, most of which are involved in the multidrug resistance phenotype. Since several ATP-binding cassette (ABC) transporters confer multidrug resistance, we correlated the IC_(50) values for berberine with the microarray-based mRNA expression values of 31 ABC transporter genes. The expression of 8 ABC transporters correlated with the IC_(50) values for berberine. Using CEMIVCR1000 leukemia cells, which over-express theABCBl (MDR1) gene, we exemplarily validated that this ABC transporter confers resistance to berberine. Furthermore, the IC5Q values for berberine of the 60 NCI cell lines were associated with microarray-based mRNA expression of 9,706 genes. By COMPARE and hierarchical cluster analyses, 20 genes were identified which significantly predicted sensitivity or resistance of the cell lines to berberine. In conclusion, the response of tumor cells to berberine is multi-factorial in nature. Novel candidate genes were identified that might determine cellular response to berberine.