β-Hydroxyisovalerylshikonin and Cisplatin Act Synergistically to Inhibit Growth and to Induce Apoptosis of Human Lung Cancer DMS114 Cells via a Tyrosine Kinase-Dependent Pathway

Abstract

β-Hydroxyisovalerylshikonin (β-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 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 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 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 of the 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 the inhibition of a tyrosine kinase-dependent pathway.

Anti-neoplastic effect of β-hydroxyisovalerylshikonin on a human choriocarcinoma cell line

“…The results of the present study indicate that β-HiVS is highly effective in suppressing the growth of β choriocarcinoma cells at a low concentration (10 -6 -10 -5 M), in agreement with the findings of previous reports (5)(6)(7)(8). The marked arrest of cancer cells in the G 0 /G 1 phase of the cell cycle is likely to account for this effect.…”

“…1), one of the derivatives of shikonin, is an aTP non-competitive inhibitor of the protein-tyrosine kinases (5), and has the strongest apoptosis-inducing activity of the shikonin derivatives (6). β-HiVS has been demonstrated to inhibit the proliferation and induce the apoptosis of tumor cells, including leukaemia (6,7), malignant melanoma (6), lung cancer (5,7,8), endometrial and ovarian cancer (9) cells, at ic 50 values ranging between 10 -6 and 10 -8 M. However, β-HiVS alone was shown to have no significant effect on the growth of human epidermoid carcinoma a431 cells at a concentration of 10 -5 M (10). The effect of β-HiVS on choriocarcinoma cells has not previously been described.…”

First Syntheses of Melophlins P, Q, and R, and Effects of Melophlins on the Growth of Microorganisms and Tumor Cells

“…This is actually better than activities for cisplatin in these cell lines as measured by us and reported in literature, i.e. IC 50 = 3.08 µM (A-498; 120 h) [19] and 6.41 µM (U-937; 48 h) [20]. The distinctly different cytotoxicities of the melophlin couples B/C and R/Q are remarkable, given their great structural similarity.…”

“…2 10 ± 1.0 9.0 ± 0.6 6.1 ± 0. b Also see ref [19]. c Not measured; ref [20] quotes an IC 50 = 6.41 µM for an MTT assay (48 h). …”

Beta-Hydroxyisovalerylshikonin Inhibits the Growth of U266 Multiple Myeloma Cells by Triggering the Mitochondrial Pathway

“…Hashimoto et al, 2002 found that beta-HIVS was able to induce cell death more efficiently in DMS114 and NCI-H522 lung cancer cells [6]. Xu et al, 2004 also presented the similar results [18]. Masuda and his study group had previously validated the effects of beta-HIVS on U937 and HL-60 leukemia cells and found both two kinds of cell lines all suffered from apoptosis when treated with 10 -6 M beta-HIVS [14].…”