Increased ubiquitination of multidrug resistance 1 by ginsenoside Rd.

MCF-7/ADR cells, a doxorubicin-resistant human breast cancer cell line, acquires resistance to several chemotherapeutic agents, such as anthracylines and taxol, via overexpression of the multidrug resistance1 (MDR1) gene. The present study was designed to clarify whether ginsenosides affect the expression of the MDR1 gene in MCF-7/ADR cells. Ginsenoside Rd, Re, Rb1, and Rg1 (100 microg/ml) decreased MDR1 protein levels in MCF-7/ADR cells. In particular, ginsenoside Rd most potently inhibited MDR1 protein expression without cytotoxicity, but did not change mRNA levels or nuclear levels of key transcriptional factors for MDR1 gene expression, hypoxia inducible factor-1alpha, CCAAT-enhancer binding protein beta, Forkhead box-containing protein, O subfamily1, or Y-box binding protein-1. Reporter gene analyses showed that ginsenoside Rd did not decrease MDR1 gene transcription or the pregnane X receptor reporter. MDR1 protein stability is dependent on ubiquitin-dependent protein degradation. We further found that ginsenosides Rd increased ubiquitination of MDR1. Moreover, doxorubicin resistance in MCF-7/ADR cells was reversed by ginsenoside Rd treatment. These results propose that ginseng administration with other anti-cancer agents may be useful for the treatment of chemotherapy-resistant breast cancer through down-regulating MDR1 protein.