Implication of tyrosine kinases and protein kinase C in dimethyl sulfoxide-induced apoptosis.

We have previously shown that the chemical agent of myeloid differentiation, dimethyl sulfoxide (DMSO), causes apoptosis in human leukemic U937 cells (Château et al. Anal. Cell. Pathol. 1996;10:75-84). Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) led to inhibition of the DMSO-induced apoptosis, suggesting that PKC helps regulate this mechanism by preventing cell death. However, specific inhibitors of PKC (bisindolylmaleimide, D sphingosine), neither triggered apoptosis themselves, nor affected the DMSO-induced apoptosis. Surprisingly, herbimycin A, a potent inhibitor of tyrosine kinases, did not trigger apoptosis itself, but it did prevent DMSO-induced nuclear fragmentation, whereas okadaic acid, an inhibitor of protein phosphatases, triggered apoptosis in U937 cells. These results suggest that DMSO-induced apoptosis requires the activation of an unidentified tyrosine kinase that is probably down-regulated by PKC activation.