Scytophycins, Novel Microfilament-depolymerizing Agents Which Circumvent P-Glycoprotein-mediated Multidrug Resistance1

Charles Smith, Gregory M.L. Patterson

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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 Scytonemataceae, 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 SKVLB1 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 SKVLB1 cells, while cytochalasin B caused only modest increases, 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.

Original languageEnglish (US)
Pages (from-to)1343-1347
Number of pages5
JournalCancer Research
Volume53
Issue number6
StatePublished - Jan 1 1993

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P-Glycoprotein
Actin Cytoskeleton
Cytochalasin B
Vinblastine
Pharmaceutical Preparations
Multiple Drug Resistance
Doxorubicin
Macrolides
Cyanobacteria
Verapamil
Biological Products
Cisplatin
Carrier Proteins
tolytoxin
Carcinoma
Phenotype

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Scytophycins, Novel Microfilament-depolymerizing Agents Which Circumvent P-Glycoprotein-mediated Multidrug Resistance1",
abstract = "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 Scytonemataceae, 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 SKVLB1 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 SKVLB1 cells, while cytochalasin B caused only modest increases, 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.",
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Scytophycins, Novel Microfilament-depolymerizing Agents Which Circumvent P-Glycoprotein-mediated Multidrug Resistance1. / Smith, Charles; Patterson, Gregory M.L.

In: Cancer Research, Vol. 53, No. 6, 01.01.1993, p. 1343-1347.

Research output: Contribution to journalArticle

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