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Screening and discovery of novel MDR modifiers from naturally occurring bisbenzylisoquinoline alkaloids
1Department of Pathology, Medical University of South Carolina, Charleston 29425, USA.
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 multidrug resistance (MDR) is to develop functional MDR modifiers that can inhibit the activity of P-gp.
Materials And Methods:
We used MTT in combination with other in vitro drug evaluation assays to screen potential MDR modifiers from a series of naturally occurring Bisbenzylisoquinoline Alkaloids (BBIs) that were isolated from natural plants.
Results:
Our in vitro screening assays indicated that at least six of these natural compounds (FF0019, FF0018, FF0015, FF0014, FF0011 and FF0012) showed potent activities to restore sensitivity of resistant tumor cells, such as MCF-7/adr and KBv200 cells, to many antitumor drugs including doxorubicin and vincristine. Further analyses by measurement of radioactive [3H]-Vincristine indicated that these BBIs increased intracellular drug accumulation in MDR cells, but had little effect on drug-sensitive cells.
Conclusions:
These results suggested that the mechanism of these compounds to reverse MDR was associated with the increase in the intracellular drug accumulation through inhibiting the activity of P-gp. Another important feature is that the in vitro cytotoxic effect of these naturally occurring BBIs themselves on tumor cells was very low. Thus, these compounds may possess great promise in being developed into novel MDR modifiers.
Insights
Naturally occurring Bisbenzylisoquinoline Alkaloids (BBIs) show promise as multidrug resistance (MDR) modifiers. These compounds restore cancer drug sensitivity by inhibiting P-glycoprotein (P-gp) efflux pumps, with low toxicity to tumor cells.
Area of Science:
- Natural Product Chemistry
- Cancer Pharmacology
- Medicinal Chemistry
Background:
- Multidrug resistance (MDR) in cancer is often caused by P-glycoprotein (P-gp) drug efflux pumps.
- Developing effective MDR modifiers is crucial for improving chemotherapy outcomes.
Purpose of the Study:
- To screen naturally occurring Bisbenzylisoquinoline Alkaloids (BBIs) for MDR modifying activity.
- To investigate the potential of BBIs as inhibitors of P-gp.
Main Methods:
- In vitro drug evaluation assays including MTT assays were employed.
- Screening of BBIs isolated from natural plants was performed.
- Intracellular drug accumulation was measured using radioactive [3H]-Vincristine.
Main Results:
- Six BBIs (FF0019, FF0018, FF0015, FF0014, FF0011, FF0012) restored sensitivity of resistant cells (MCF-7/adr, KBv200) to anticancer drugs.
- BBIs increased intracellular drug accumulation in MDR cells.
- BBIs exhibited low in vitro cytotoxicity against tumor cells.
Conclusions:
- BBIs reverse MDR by inhibiting P-gp activity, leading to increased intracellular drug accumulation.
- Naturally occurring BBIs demonstrate potential as novel MDR modifiers with favorable safety profiles.