Aspergillus species strain M39 produces two naphtho-gamma-pyrones that reverse drug resistance in human KB cells.
One thousand fungi and Actinomycetes were investigated to see whether they produced compounds that reverse multi-drug resistance in KB cells. Only one Aspergillus strain M39 produced agents with resistance-reversing activity and these compounds were identified to be rubrofusarin B and dianhydro-aurasperone C. Rubrofusarin B only slightly reversed the resistance of KB-C2 cells to Adriamycin and daunomycin, partially reversed the resistance to chromomycin A3, and almost completely reversed the resistance to vincristine and mitomycin C. Purified dianhydro-aurasperone C and rubrofusarin B had similar effects on drug resistance in KB-8-5 cells. Dianhydro-aurasperone C enhanced the accumulation of vinblastine in KB-8-5 cells and inhibited the efflux of vinblastine from the cells. Dianhydro-aurasperone C and rubrofusarin B at 10 microM completely inhibited 3H-azidopine photolabelling of P-glycoprotein. The two products of Aspergillus strain M39 appear to reverse multi-drug resistance by interacting with P-glycoprotein and inhibiting its role as an active efflux pump.
Ikeda
S
S
Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.
Sugita
M
M
Yoshimura
A
A
Sumizawa
T
T
Douzono
H
H
Nagata
Y
Y
Akiyama
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001230:Aspergillus / Q000378:metabolism*; D001386:Azides / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009284:Naphthols / Q000378:metabolism / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D011753:Pyrones / Q000378:metabolism / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001386:Azides; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; D009284:Naphthols; D011714:Pyrans; D011753:Pyrones; C015497:rubrofusarin; D014747:Vinblastine; C041130:azidopine; D004317:Doxorubicin; C063315:dianhydroaurasperone C; D014700:Verapamil