Beta-hydroxyisovalerylshikonin and cisplatin act synergistically to inhibit growth and to induce apoptosis of human lung cancer DMS114 cells via a tyrosine kinase-dependent pathway

beta-Hydroxyisovalerylshikonin (beta-HIVS) and cisplatin (CDDP) had a synergistic growth-inhibitory effect on cultured human small-cell lung carcinoma DMS114 cells, as well as on human leukemia U937 and epidermoid carcinoma A431 cells, while beta-HIVS and CDDP alone at the same respective concentrations had little effect. Growth inhibition was accompanied by induction of apoptosis, as determined by an ELISA for the detection of cell death and the TUNEL assay. Using phosphotyrosine-specific antibodies (PY20), we observed that tyrosine kinase activity in DMS114 cells was inhibited by treatment with beta-HIVS and CDDP together. The tyrosine kinase activity of isolated Src and that of isolated receptors for epidermal growth factor were also inhibited by the two agents together. The synergistic effects of the growth of DMS114 cells of beta-HIVS and CDDP were not due simply to the intracellular accumulation of CDDP or to levels of DNA adducts. Our data suggest that the synergistic effect on the growth of DMS114 cells of beta-HIVS and CDDP might be a result of the inhibition of a tyrosine kinase-dependent pathway.