WELWITINDOLINONE ANALOGS THAT REVERSE P-GLYCOPROTEIN-MEDIATED MULTIPLE-DRUG RESISTANCE

Welwitindolinones are a family of novel alkaloids recently isolated fr om the blue-green alga Hapalosiphon welwitschii as a part of our effor t to identify new compounds that overcome multiple drug resistance. Th e abilities of three structurally similar members of this family to in teract with P-glycoprotein have been compared. Similarly to the effect s of verapamil, N-methylwelwitindolinone C isothiocyanate (compound 1) attenuated the resistance of MCF-7/ADR cells to natural product antic ancer drugs, including vinblastine, taxol, actinomycin D, daunomycin, and colchicine, without affecting the cytotoxicity of cisplatin. These effects of compound 1 were apparent at doses as low as 0.1 mu M, indi cating that it is considerably more potent than verapamil for reversal of resistance. Welwitindolinone C isothiocyanate (compound 3) demonst rated weaker reversing activity, whereas an analogue of compound 1 in which the isothiocyanate group is replaced by an isonitrile group (com pound 2) was inactive. The accumulation of [H-3]vinblastine in SK-VLB- 1 cells was increased by compound 1 > compound 3 > verapamil >> compou nd 2. Interestingly, only compound 1 and verapamil enhanced [H-3]taxol accumulation by these cells. Photoaffinity labeling of P-glycoprotein with [H-3]azidopine in membranes from SK-VLB-1 cells was inhibited by compounds 1 and 3, but not by compound 2. Therefore, the difference's in the size and/or the electronegativity of the isothiocyanate and is onitrile moieties appear to dramatically affect the abilities of the c ompounds to interact with P-glycoprotein.