REVERSAL OF MULTIPLE-DRUG RESISTANCE BY TOLYPORPHIN, A NOVEL CYANOBACTERIAL NATURAL PRODUCT

The effects of a novel porphyrin, tolyporphin, on P-glycoprotein-media ted multiple drug resistance in human ovarian and breast cell lines we re 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. Subto xic doses of tolyporphin increased the sensitivity of the SKVLB1 and M CF-7/ADR cells to P-glycoprotein-transported drugs, but did not increa se the antiproliferative effects of nontransported drugs. Tolyporphin also enhanced the accumulation of [H-3]-vinblastine in SKVLB1 and MCF- 7/ADR cells at doses approximately 10-fold lower than those required f or similar responses to verapamil. In contrast, tolyporphin did not af fect drug accumulation in SKOV3 or MCF-7 cells. Tolyporphin reduced [H -3]-vinblastine efflux from SKVLB1 cells, reduced [H-3]-vinblastine bi nding to membranes from SKVLB1 cells, and blocked the ability of [H-3] -azidopine to photoaffinity-label P-glycoprotein in these membranes. T hese results indicate that tolyporphin binds to P-glycoprotein and inh ibits the transport of cytotoxic natural product drugs. This novel nat ural product, and related compounds, may be useful for the reversal of multiple drug resistance and for further definition of the drug bindi ng site(s) of P-glycoprotein.