Reversal of multiple drug resistance by tolyporphin, a novel cyanobacterial natural product.
The effects of a novel porphyrin, tolyporphin, on P-glycoprotein-mediated multiple drug resistance in human ovarian and breast cell lines were characterized. Compared with parental SKOV3 and MCF-7 cells, the P-glycoprotein-overexpressing sublines SKVLB1 and MCF-7/ADR were 5- and 1.3-fold less sensitive to the cytotoxic effects of tolyporphin. Subtoxic doses of tolyporphin increased the sensitivity of the SKVLB1 and MCF-7/ADR cells to P-glycoprotein-transported drugs, but did not increase the antiproliferative effects of nontransported drugs. Tolyporphin also enhanced the accumulation of [3H]-vinblastine in SKVLB1 and MCF-7/ADR cells at doses approximately 10-fold lower than those required for similar responses to verapamil. In contrast, tolyporphin did not affect drug accumulation in SKOV3 or MCF-7 cells. Tolyporphin reduced [3H]-vinblastine efflux from SKVLB1 cells, reduced [3H]-vinblastine binding to membranes from SKVLB1 cells, and blocked the ability of [3H]-azidopine to photoaffinity-label P-glycoprotein in these membranes. These results indicate that tolyporphin binds to P-glycoprotein and inhibits the transport of cytotoxic natural product drugs. This novel natural product, and related compounds, may be useful for the reversal of multiple drug resistance and for further definition of the drug binding site(s) of P-glycoprotein.
Smith
C D
CD
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111.
Prinsep
M R
MR
Caplan
F R
FR
Moore
R E
RE
Patterson
G M
GM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000345:Affinity Labels; D001692:Biological Transport; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000458:Cyanobacteria / Q000737:chemistry; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology*; D014316:Tritium; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D011166:Porphyrins; C091793:tolyporphin; D014316:Tritium; D014747:Vinblastine