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Scytophycins, novel microfilament-depolymerizing agents which circumvent P-glycoprotein-mediated multidrug resistance
C D Smith1, S Carmeli, R E Moore
1Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813.
Cancer Research
|March 15, 1993
Summary
Certain natural compounds called scytophycins, including tolytoxin, are effective against multidrug-resistant cancer cells. These compounds bypass P-glycoprotein pumps, offering potential for treating resistant tumors.
Area of Science:
- Natural Product Chemistry
- Cell Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) in cancer cells, often due to P-glycoprotein (P-gp) overexpression, limits chemotherapy efficacy.
- Scytophycins are natural cytotoxic macrolides from cyanobacteria with potential anticancer activity.
Purpose of the Study:
- To investigate if P-glycoprotein confers resistance to scytophycins in human ovarian carcinoma cells.
- To evaluate the potential of scytophycins, like tolytoxin, as agents against P-gp-mediated MDR.
Main Methods:
- Characterized antiproliferative effects of scytophycins on drug-sensitive (SKOV3) and P-gp overexpressing (SKVLB1) ovarian cancer cells.
- Assessed microfilament depolymerization by scytophycins and other agents.
- Measured drug accumulation in SKVLB1 cells using radiolabeled compounds and modulators like verapamil.
Main Results:
- SKVLB1 cells showed high resistance to Adriamycin and vinblastine but similar sensitivity to tolytoxin compared to SKOV3 cells.
- Tolytoxin and related scytophycins were not subject to P-gp-mediated efflux, unlike cytochalasin B.
- Tolytoxin did not affect [3H]vinblastine accumulation in SKVLB1 cells, indicating it bypasses P-gp.
Conclusions:
- Tolytoxin and some scytophycins are not substrates for P-glycoprotein efflux pumps.
- These scytophycins demonstrate potential as therapeutic agents for overcoming P-gp-mediated multidrug resistance in cancer.