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 multidrug resistance (MDR) is to develop functional MDR modifiers that can inhibit the activity of P-gp.


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.
Fu
L W
LW
Department of Pathology, Medical University of South Carolina, Charleston 29425, USA.
Deng
Z A
ZA
Pan
Q C
QC
Fan
W
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000470:Alkaloids / Q000494:pharmacology* / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology* / Q000633:toxicity; D007624:KB Cells / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D007546:Isoquinolines; D014750:Vincristine; D004317:Doxorubicin