herbimycin and Lung-Neoplasms

In our previous studies (S. Simizu, et al., 1996, Cancer Res. 56, 4978-4982), we reported that apoptosis of human small cell lung carcinoma (SCLC) cells induced by protein tyrosine kinase inhibitors, such as erbstatin and herbimycin A, was mediated by H2O2 via a newly synthesized protein(s). In the present study, we demonstrated that induction of apoptosis by erbstatin resulted in activation of caspase-3(-like) proteases, which are interleukin-1 beta-converting enzyme family proteases (caspases) and that inhibition of these protease activities reduced the extent of cell death and H2O2 generation. We also demonstrated that expression of apoptotic protein Bax was induced by erbstatin. Erbstatin-induced Bax expression was inhibited by the inhibitor of caspase-3(-like) proteases. These results indicate that generation of intracellular H2O2 and Bax expression in tyrosine kinase inhibitor-induced apoptosis were modulated by the activation of caspase-3(-like) proteases in SCLC cells.

Topics: Apoptosis; bcl-2-Associated X Protein; Benzoquinones; Carcinoma, Small Cell; Caspase 3; Caspases; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Enzyme Activation; Enzyme Inhibitors; Enzyme Precursors; Humans; Hydrogen Peroxide; Hydroquinones; Kinetics; Lactams, Macrocyclic; Lung Neoplasms; Oligopeptides; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Quinones; Rifabutin; Tumor Cells, Cultured

Benzimidazole compounds, such as omeprazole and thiabendazole, are a different type of CYP1A1 inducer from Ah receptor-ligands, such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and 3-methylcholanthrene. In HepG2 cells, the commonly used tyrosine kinase inhibitors, herbimycin-A and a series of tyrphostins, inhibited the induction of CYP1A1 produced by treatment with TCDD. Genistein, another type of tyrosine kinase inhibitor, inhibited the induction of CYP1A1 whether it was produced by omeprazole or TCDD; however, this inhibition was caused by a dual effect of genistein, that is an anti-tyrosine kinase and an anti-topoisomerase I effect. An antagonist of Ah receptor, alpha-naphthoflavone (0.1-10 microM), and 3'-methoxy-4'-aminoflavone (1 microM), did not inhibit the induction of CYP1A1 produced in HepG2 cells by omeprazole, but both of them did inhibit that produced by TCDD. In one of a number of human lung tumor cell lines, S6T, the inducibility of CYP1A1 was high by TCDD, whereas the inducibility by omeprazole was low. Thus, omeprazole appears to induce CYP1A1 by initiating a protein tyrosine kinase-mediated signal transduction pathway, a different pathway from that inhibited by TCDD.

Topics: Benzoflavones; Benzoquinones; Carcinoma, Hepatocellular; Cytochrome P-450 CYP1A1; DNA Topoisomerases, Type I; Enzyme Induction; Enzyme Inhibitors; Humans; Lactams, Macrocyclic; Lung Neoplasms; Omeprazole; Polychlorinated Dibenzodioxins; Protein Binding; Protein-Tyrosine Kinases; Quinones; Receptors, Aryl Hydrocarbon; Regulatory Sequences, Nucleic Acid; Rifabutin; RNA, Messenger; Tumor Cells, Cultured

IMR32, a neuroblastoma cell line, and CADO LC6, a small cell lung cancer (SCLC) cell line, extended neurite-like processes when cultured on fibronectin (FN)-coated surfaces or cultured in a serum-free medium. Monoclonal antibodies against the integrin beta 1 subunit inhibited this process formation, suggesting that their morphological change is initiated by beta 1 integrin-dependent signal transduction to the cell interior. Anti-phosphorylation level of a 100-kDa protein, but not 125-kDa focal adhesion kindase, correlated well with the morphological change in both cell lines. This 100-kDa protein phosphorylation did not accompany FN-induced morphological changes in NIH 3T3 fibroblasts or A549 adenocarcinoma cells. These findings suggest that neuroblastoma and SCLC may share beta 1 integrin-mediated signaling events distinct from nonneuronal cells.

Topics: Adenocarcinoma; Benzoquinones; Blotting, Western; Carcinoma, Small Cell; Cell Adhesion; Cell Adhesion Molecules; Cell Differentiation; Enzyme Inhibitors; Flow Cytometry; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Integrin beta1; Lactams, Macrocyclic; Lung Neoplasms; Neuroblastoma; Phosphorylation; Protein-Tyrosine Kinases; Quinones; Receptor, Insulin; Rifabutin; Signal Transduction; Tumor Cells, Cultured; Tyrosine