Multidrug-resistant human kb carcinoma cells are highly resistant to the protein phosphatase inhibitors okadaic acid and calyculin A. Analysis of potential mechanisms involved in toxin resistance
✍ Scribed by Timothy C. Chambers; Robert L. Raynor; J. F. Kuo
- Publisher
- John Wiley and Sons
- Year
- 1993
- Tongue
- French
- Weight
- 750 KB
- Volume
- 53
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
In this study we show that multidrug-resistant (MDR) human KB-VI cells are highly resistant to the cytotoxicity of okadaic acid and calyculin A, 2 toxins from marine sponges that are potent inhibitors of type-I and type-2A protein phosphatases (PPl and PP2A). Cytotoxicity and colony-forming assays indicated that, relative to parental drug-sensitive KB-3 cells, KB-VI cells are 35-fold more resistant to okadaic acid and 70-fold more resistant to calyculin A. Cytotoxicity of the toxins was associated with mitotic arrest characterized by chromosome scattering and over-condensation, with KB-3 cells being more sensitive than KB-VI cells and calyculin A being more potent than okadaic acid. The resistance of KB-VI cells to both okadaic acid and calyculin A was completely reversed by verapamil, suggesting that the toxins may be transported by P-glycoprotein (P-gp). To further assess the possibility of an interaction with P-gp, the toxins were employed as potential modulators of the photoaffinity labeling of P-gp by C3H]azidopine. Relative to vinblastine, which effectively competed with [3H]azidopine for P-gp photolabeling, calyculin A was 100-fold less potent and 'To whom correspondence and reprint requests should be addressed.