Screening and discovery of novel MDR modifiers from naturally occurring bisbenzylisoquinoline alkaloids

Background. The failure of conventional cancer chemotherapy has been linked to overexpression of a membrane associated P-glycoprotein (P-gp) that acts as an energy-dependent drug efflux pump. A promising strategy to conquer m ultidrug resistance (MDR) is to develop functional MDR modifiers that can i nhibit the activity of P-gp. Materials and Methods. We used MTT in combinat ion with other in vitro drug evaluation assays to screen potential MDR modi fiers from a series of naturally occurring Bisbenzylisoquinoline Alkaloids (BBIs) that were isolated from natural plants. Results. Our in vitro screen ing assays indicated that at least six of these natural compounds (FF0019, FF0018, FF0015, FF0014, FF0011 and FF0012) showed potent activities to rest ore sensitivity of resistant tumor cells, such as MCF-7/adr and KBv200 cell s, to many antitumor drugs including doxorubicin and vincristine. Further a nalyses by measurement of radioactive [H-3]-Vincristine indicated that thes e BBIs increased intracellular drug accumulation in MDR cells, but had litt le effect on drug-sensitive cells. Conclusions. These results suggested tha t the mechanism of these compounds to reverse MDR was associated with the i ncrease in the intracellular drug accumulation through inhibiting the activ ity of P-gp. Another important feature is that the in vitro cytotoxic effec t of these naturally occurring BBIs themselves on tumor cells was very low. Thus, these compounds may possess great promise in being developed into no vel MDR modifiers.