Cytotoxicity and p-glycoprotein modulating effects of quinolones and indoloquinazolines from the Chinese herb Evodia rutaecarpa.
The antimycobacterial quinolones 1-methyl-2-undecyl-4-quinolone, dihydroevocarpine and evocarpine as well as the indoloquinazoline alkaloids rutaecarpine and evodiamine - all from the Chinese medicinal herb Evodia rutaecarpa - were tested in two in vitro assays, for cytotoxicity and interaction with p-glycoprotein (p-gp). Cytotoxicity was measured in a cell proliferation assay against CCRF-CEM leukemia cells and their p-gp over-expressing subline CEM/ADR5000. An assay monitoring the p-gp-dependent accumulation of the dye calcein in porcine brain capillary endothelial cells (PBCECs) was used to study interactions of the test substances with this efflux pump. Rutaecarpine and evodiamine showed quite high toxicity with IC (50) values from 2.64 to 4.53 microM and were weak modulators of p-gp activity. The degrees of resistance in CEM/ADR5000 towards the saturated quinolones 1-methyl-2-undecyl-4-quinolone and dihydroevocarpine were between 3 and 4. In the calcein assay, these two quinolones were shown to be moderate modulators of p-gp activity. Evocarpine, on the other side, is not transported by p-gp, and showed only slight toxicity at the highest test concentration of 30 microM.
Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
Michael
M
Adams
Anne
A
Mahringer
Olaf
O
Kunert
Gert
G
Fricker
Thomas
T
Efferth
Rudolf
R
Bauer
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000166:cytology; D032086:Evodia; D006801:Humans; D045563:Indolequinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008516:Medicine, Chinese Traditional; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D045563:Indolequinones; D010936:Plant Extracts; D015363:Quinolones