Hyperforin modulation of drug resistance: Saint or sinner?

The use of medicinal plants dates back to prehistoric times. In the modern era, the use of plant compounds has expanded into cancer therapy. Compounds derived from plants are among the most important therapeutic agents in current use, and include vincristine, taxol, and etoposide. The efficacy of these drugs attests to the fact that, despite their apparently innocuous source (flowers, tree bark), plant-derived compounds are potent and can be highly toxic. St. John’s wort (SJW) is one of the most frequently purchased ‘‘natural products’’ available, used for treatment of depression and other ailments. Hyperforin is one of several pharmacologically active compounds in SJW. In this issue, Quiney et al. [1] report the potential use of hyperforin in hematooncology as a reverser of drug resistance and maximizer of cell kill by chemotherapy. They demonstrate that hyperforin inhibits P-glycoprotein (Pgp) activity, without increasing mRNA levels. Pgp is the protein encoded by the multidrug resistance gene MDR1 which functions as an ATP-dependent ‘‘efflux pump. ’’ It is expressed not infrequently in CLL [2] and may contribute to drug resistance when anthracyclines and/or vincristine are used. Furthermore, Quiney and colleagues report that hyperforin increases cell kill using an MTT assay with mitoxantrone, which is a Pgp substrate. In addition, they demonstrate inhibition of Pgp and the breast cancer resistance protein BCRP in a myeloid leukemia cell line. Kolb’s group has published a number of studies which enthusiastically point toward a potential valuable role for hyperforin in treating hematological malignancies (Reviewed in Quiney, 2006) [3]. In particular, in CLL cells, these investigators have found proapoptotic and antiangiogenic effects [3], which may have therapeutic value in treating the lymphoproliferative disorders. These results seem at first glance to be at odds with previous studies, which demonstrated upregulation of Pgp particularly in intestinal epithelial cells, leading to reduced absorption, and loss of clinical efficacy of various drugs [4]. Indeed, SJW is the most frequently reported herbal product causing serious interactions with prescription drugs, accounting for nearly 80% of several hundred case reports [5]. Such adverse effects due to drug interactions may be life threatening. Reports implicating SJW in reduced drug efficacy have included rejection of heart transplants due to reduced cyclosporine A levels and increased HIV viral load due to reduced levels of antiretroviral drugs [5]. In these cases, the mechanism involved in the induction of the drug metabolizing enzyme CP3A4 as well as the induction of Pgp, due to binding of hyperforin to PXR (pregnane X receptor), which upregulates both CYP3A4 and Pgp. Hyperforin is a high affinity ligand of PXR, and PXR caused induction of CYP3A4 which metabolically degrades the medication, while it also is more rapidly effluxed by Pgp. The paradoxical ability to both increase and decrease Pgp activity seems to be due to two different mechanisms. Short-term exposure of cells to hyperforin, together with a drug which is a Pgp substrate, will increase drug efficacy due to reduced efflux from the cell by Pgp, due to hyperforin’s effect as a Pgp inhibitor. In contrast, long-term exposure in particular by the oral route, will induce interestinal Pgp and thus reduce bioavailability and drug efficacy. It is reassuring that Quiney et al. did not find evidence of Pgp induction in CLL on exposure of cells to hyperforin for several days [1].