Doxorubicin-resistant LoVo adenocarcinoma cells display resistance to apoptosis induction by some but not all inhibitors of ser thr phosphatases 1 and 2A

LoVo adenocarcinoma cells are fairly sensitive to cytostatic drugs, e.g, do xorubicin, but can develop drug resistance by expression of a P-glycoprotei n-mediated MDR1 phenotype. LoVo cells respond with apoptosis to nanomolar c oncentrations of okadaic acid and micromolar concentrations of cantharidic acid. Interestingly, LoVoDx cells which had become about 10-fold less sensi tive to doxorubicin by incubation in increasing concentrations of this cyto static drug were also less sensitive to the: toxicity of okadaic acid. Resi stance to both agents was lost or significantly reduced by incubation in dr ug-free medium for about 4 months. On the other hand, LoVoDx cells did not lose responsiveness to the structurally different phosphatase inhibitor can tharidic acid but were about twofold more sensitive to the cytotoxic effect of this agent. Thus, MDR expression protects LoVo cells from the toxicity of phosphatase inhibitors that presumably are substrates of the P-glycoprot ein, e.g. okadaic acid and its derivatives but not cantharidic acid, despit e the fact that both agents are potent inducers of apoptotic cell death via ser/thr phosphatase inhibition. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.