TYRPHOSTIN INDUCES NON-APOPTOTIC PROGRAMMED CELL-DEATH IN COLON-TUMORCELLS

The programmed cell death inducing effect of the EGF receptor tyrosine kinase inhibitor alpha-cyano-3,4-dihydroxycinnamthioamide (AG213) was investigated in vitro on HT-29 human colon tumor. AG213 at concentrat ions between 45 to 450 mu M blocks the proliferation of HT-29 cells. M orphological findings suggest that the selective tyrosine kinase inhib itor AG213 induces Clarke III type (non-lysosomal vesiculate cytoplasm ic) programmed cell death; unlike ATP analog nonselective tyrosine kin ase inhibitors like Genistein which were found to induce apoptosis. Cy cloheximide and Actinomycin-D reduced the effect of AG213 pointing to the fact that protein and RNA synthesis are also needed for this form of cell death. Acid phosphatase activity was found in the Golgi and in the newly formed intracytoplasmic vacuoles 3 hours after AG213 treatm ent which disappeared by 6 hours. The induction of Clarke III cell dea th by tyrosine kinase inhibitors may open a new modality to selective killing of tumor cells.