Hyperforin, a major lipophilic constituent of St. John's wort, enhances paclitaxel sensitivity in HER2 overexpressing breast cancer cells.

LB-323

Hyperforin, a polyprenylated acylphloroglucinol derivative from Hypericum perforatum (St. John’s wort), modulates cytochrome P450 3A4 (CYP3A4) expression mediated by the pregnane X receptor (PXR). CYP3A4 is one of the predominant enzymes for paclitaxel metabolism, suggesting that it might be associated with a low response rate to paclitaxel. Hyperforin is also reported to enhance expression of p-glycoprotein (MDR1). Increased expression of MDR1 is one of the main mechanisms for doxorubicin resistance. Moreover, hyperforin has antitumoral activity by, at least, inducing apoptosis and inhibiting angiogenesis. In this study, we tested drug-drug interaction of hyperforin-paclitaxel in HER-2 low- (MCF-7) and high-expressing (MCF-7/HER2-18 and SK-Br-3) breast cancer cells. Drug sensitivity was measured using a standard colorimetric MTT (3-4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide) assay. The drug-drug interaction was accessed using Isobologram analysis. While hyperforin alone caused a concentration-dependent inhibition on viability, MCF-7 cells were slightly, but significantly, more sensitivity. MCF-7/HER2-18 and SK-Br-3 cells were significantly less sensitive to paclitaxel. Interestingly, hyperforin extensively enhanced the sensitivity to paclitaxel specifically in HER2-overexpressing cells. Although the mechanisms for chemosensitizing effects of hyperforin is still under investigation, our observation regarding to synergistic effects of hyperforin with paclitaxel would provide hopeful approach to improve efficacy of current chemotherapeutics in multidrug resistant breast cancer.