Development of a novel anti-cancer agent from a novel tyrosine kinase inhibitor

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We reported previously that β-hydroxyisovalerylshikonin (β-HIVS), isolated from the plant Lithospermium radix, inhibits protein tyrosine kinase activites of EGFR and v-Src. In an effort to enhance the antMumor activity of β-HIVS, we examined the effects of various combinations of β-HIVS with anti-tumor agents on human small-cell lung carcinoma DMS114. β-HIVS and cisplatin (CDDP) had a synergistic inhibitory effect on DMS114 cells, as well as on human leukemia U937 and epidermoid carcinoma A431 cells, while β-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 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 β-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 on growth of DMS114 cells of β-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 β-HIVS and CDDP might be a result of inhibition of a tyrosine kinase-dependent pathway.