Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance.
Welwitindolinones are a family of novel alkaloids recently isolated from the blue-green alga Hapalosiphon welwitschii as a part of our effort to identify new compounds that overcome multiple drug resistance. The abilities of three structurally similar members of this family to interact with P-glycoprotein have been compared. Similarly to the effects of verapamil, N-methylwelwitindolinone C isothiocyanate (compound 1) attenuated the resistance of MCF-7/ADR cells to natural product anticancer 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 microM, indicating that it is considerably more potent than verapamil for reversal of resistance. Welwitindolinone C isothiocyanate (compound 3) demonstrated weaker reversing activity, whereas an analogue of compound 1 in which the isothiocyanate group is replaced by an isonitrile group (compound 2) was inactive. The accumulation of [3H]vinblastine in SK-VLB-1 cells was increased by compound 1 > compound 3 > verapamil >> compound 2. Interestingly, only compound 1 and verapamil enhanced [3H]taxol accumulation by these cells. Photoaffinity labeling of P-glycoprotein with [3H]azidopine in membranes from SK-VLB-1 cells was inhibited by compounds 1 and 3, but not by compound 2. Therefore, the differences in the size and/or the electronegativity of the isothiocyanate and isonitrile moieties appear to dramatically affect the abilities of the compounds to interact with P-glycoprotein.
Smith
C D
CD
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Zilfou
J T
JT
Stratmann
K
K
Patterson
G M
GM
Moore
R E
RE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000502:physiology*; D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D018432:Drug Resistance, Multiple; D026121:Indole Alkaloids; D011485:Protein Binding; D014316:Tritium; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000970:Antineoplastic Agents; D026121:Indole Alkaloids; C092268:N-methylwelwitindolinone C isothiocyanate; C092269:N-methylwelwitindolinone C nitrile; C092270:welwitindolinone C isothiocyanate; D014316:Tritium