Anti-proliferative effects of ginsenosides on multidrug resistant cancer cell lines

Jing Jin1, Emma Yeung1, Margery Barrand1, Ricky Ngok Shun Wong2, Tai-Ping Fan1. 1Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK and 2Department of Biology, Hong Kong Baptist University, Hong Kong SAR, China.

Multi-drug resistance (MDR), which often develops in the cancer cells of patients receiving anti-cancer treatment, is a major obstacle for successful chemotherapy (Lee 2004). Although many inhibitors of MDR transporters have been identified and some are undergoing clinical trials, the existence of multiple ATP-binding cassette (ABC) transporters and/or MDR mechanisms other than those mediated by ABC transporters hinder the successful reversal of clinical MDR. Therefore, there has been great interest in identifying novel anti-cancer agents that can bypass MDR mechanisms.

Ginseng is one of the most widely used natural tonics in oriental countries for two thousand years. Many of its pharmacological actions are attributed to the ginsenosides (Shibata 2001). Here we report the anticancer activity, especially anti-MDR-cancer activity, and molecular mechanisms of action of 6 ginsenosides. As determined by MTT assay, protopanaxadiol Rg3 (100µM) and protopanaxatriols Rg1 (100µM) and Rh1 (50µM) did not show anti-proliferative activities in a panel of sensitive and MDR cancer cell lines. However, the sugarless protopanaxadiol PPD was the most potent in inhibiting the growth of these cells with IC50s in the range from 20 to 30µM, followed by ginsenoside Rh2 (with the IC50s from 25 to 40µM), and the sugarless protopanaxatriol PPT (with the IC50s between 35 to 50µM). Exposure to PPD induced the loss of mitochondrial membrane potential, release of cytochrome c into cytosol, activation of caspases 3, 8 and 9, inhibition of Bcl-2 level, cleavage of Bid, and generation of reactive oxygen species (ROS), indicating the involvement of both intrinsic and extrinsic apoptotic pathways. In contrast, the reduction in Bcl-2 expression, caspase 9 activation or ROS generation was not obvious after Rh2 treatment, but all were significant after PPT treatment, suggesting Rh2 and PPT induce apoptosis through extrinsic and intrinsic pathway, respectively. Furthermore, ROS generation was notable in mitoxantrone (MX)-resistant MCF-7/MX breast cancer cells exposed to PPD and PPT, but not in MX-sensitive MCF-7 cells. RT-PCR results showed that MCF-7/MX cells expressed higher level of manganese superoxide dismutase (MnSOD) and similar level of catalase compared to MCF-7 cells. The imbalanced expression of MnSOD and catalase in MCF-7/MX cells could lead to impaired detoxicification of the excessive ROS induced by PPD, contributing to the hypersensitivity of MCF-7/MX cells to PPD.

Further studies on the structure-activity relationship of ginsenosides will be helpful to the synthesis of novel PPD derivatives with improved pharmacodynamic and pharmacokinetic properties for effective treatment of cancer, especially MDR cancer.

Lee CH (2004) Curr Med Chem Anti-Canc Agents 4:43-52.
Shibata S (2001) J Korean Med Sci 16:S28-S37.

We thank NuLiv Science Taiwan and Hong Kong RGC (HKBU 2171/03M) for financial support, and Professor Rik Scheper, Free University, the Netherlands for the MCF-7/MX cells.