Scytophycins, novel microfilament-depolymerizing agents which circumvent P-glycoprotein-mediated multidrug resistance.
Cells demonstrating the multidrug resistance phenotype because of overexpression of P-glycoprotein, a drug efflux pump, are resistant to the cytotoxic effects of most natural product drugs. To determine if P-glycoprotein confers resistance to the syctophycins, a family of natural cytotoxic macrolides recently isolated from cyanobacteria of the family Syctone-mataceae, we have characterized the effects of these compounds on drug-sensitive (SKOV3) and drug-resistant (SKVLB1) human ovarian carcinoma cells. While SKVLB1 cells demonstrated > 150- and 10,000-fold decreases in sensitivity to Adriamycin and vinblastine, respectively, they were equally sensitive as SKOV3 cells to the antiproliferative effects of tolytoxin and certain related scytophycins. The SKVKB1 cells were 4- to 11-fold resistant to other scytophycins and were 14-fold resistant to cytochalasin B. Microfilaments in SKOV3 and SKVLB1 cells were depolymerized by similar concentrations of tolytoxin, while cytochalasin B was less potent toward SKVLB1 cells than SKOV3 cells. Both tolytoxin and cytochalasin B enhanced the cytotoxicity of vinblastine toward SKVLB1 cells; however, neither compound affected the sensitivity to Adriamycin or cisplatin. Verapamil markedly increased the accumulation of [3H]vinblastine by SKLVB1 cells, while cytochalasin B caused only modest increase, and tolytoxin had no effect on [3H]vinblastine accumulation. These results suggest that some of the scytophycins, including tolytoxin, are not subject to P-glycoprotein-mediated efflux from cells exhibiting multidrug resistance due to overexpression of this transport protein. These compounds may therefore be useful for killing drug-resistant tumor cells.
Smith
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CD
Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813.
Carmeli
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Moore
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Patterson
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GM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008841:Actin Cytoskeleton / Q000187:drug effects*; D000199:Actins / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000458:Cyanobacteria / Q000737:chemistry*; D003571:Cytochalasin B / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000473:pathology; D011714:Pyrans / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000199:Actins; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D011714:Pyrans; C080064:scytophycin B; C080065:scytophycin A; C080066:scytophycin D; C080063:scytophycin E; C068527:tolytoxin; D003571:Cytochalasin B; D014747:Vinblastine