Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells.

There is considerable interest among basic and clinical researchers in novel drugs with activity against leukemia. The vast history of experience of traditional Chinese medicine (TCM) with medicinal plants may facilitate the identification of novel antileukemic compounds. In the present investigation, we tested 22 drugs for their activity toward CCRF-CEM cell lines: artesunate, artemisinin, baicalein, baicalin, berberine, bufalin, cantharidin, cephalotaxine, curcumin, daidzein, daidzin, diallyl disulfide, ginsenoside Rh2, glycyrrhizic acid, isonardosinon, homoharringtonine, nardosinon, nardofuran, puerarin, quercetin, tannic acid, and tetrahydronardosinon. As compounds from folk medicinal remedies are sometimes looked upon as alternative medicine with some hesitation or criticism, we investigated only chemically pure compounds and tested the drugs independently in two different laboratories in Germany and Australia. We used CCRF-CEM parental cells and doxorubicin-selected P-glycoprotein (P-gp)/MDR1-expressing CEM/ADR5000, vinblastine-selected P-gp/MDR1-expressing CEM/VLB(100), and epirubicin-selected multidrug resistance-related protein 1 (MRP1)-expressing CEM/E1000 sublines thereof. While CEM/ADR5000, CEM/VLB(100), and CEM/E1000 cells were highly resistant to the corresponding selecting agents, no or only minimal degrees of cross-resistance were observed to TCM drugs in both growth inhibition assay and MTT assay (range from 0.4- to 8-fold). Homoharringtonine, artesunate, and bufalin were most active among this panel of compounds. As shown by flow cytometry, artesunate significantly increased daunorubicin accumulation in CEM/E1000 cells, but not in CEM/VLB(100) or CCRF-CEM parental cells. Bufalin caused a small, but significant increase in daunorubicin accumulation in CEM/VLB(100) and CEM/E1000 cells. As artesunate and bufalin showed both antileukemic activity if applied alone and modulation activity in combination with daunorubicin in multidrug-resistant (MDR) cells, these two drugs may be suitable for novel combination treatment regimens to improve leukemia cell killing.