Doxorubicin-resistant LoVo adenocarcinoma cells display resistance to apoptosis induction by some but not all inhibitors of ser thr phosphatases 1 and 2A
S. Sieder et al., Doxorubicin-resistant LoVo adenocarcinoma cells display resistance to apoptosis induction by some but not all inhibitors of ser thr phosphatases 1 and 2A, TOXICOLOGY, 134(2-3), 1999, pp. 109-115
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.