benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Carcinoma--Small-Cell

Apoptosis, a tightly controlled multi-step mechanism of cell death, is important for anti-cancer therapy-based elimination of tumor cells. However, this process is not always efficient. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cells display different susceptibility to undergo apoptosis induced by anticancer treatment. In contrast to SCLC, NSCLC cells are cross-resistant to a broad spectrum of apoptotic stimuli, including receptor stimulation, cytotoxic drugs and gamma-radiation. Since resistance of tumor cells to treatment often accounts for the failure of traditional forms of cancer therapy, in the present study attempts to find a potent broad-range apoptosis inductor, which can kill therapy-resistant NSCLC cells were undertaken and the mechanism of apoptosis induction by this drug was investigated in detail. We found that staurosporine (STS) had cell killing effect on both types of lung carcinomas. Release of cytochrome c, activation of apical and effector caspases followed by cleavage of their nuclear substrates and morphological changes specific for apoptosis were observed in STS-treated cells. In contrast to treatment with radiation or chemotherapy drugs, STS induces mitochondrial dysfunction followed by translocation of AIF into the nuclei. These events preceded the activation of nuclear apoptosis. Thus, in lung carcinomas two cell death pathways, caspase-dependent and caspase-independent, coexist. In NSCLC cells, where the caspase-dependent pathway is less efficient, the triggering of an AIF-mediated caspase-independent mechanism circumvents the resistance of these cells to treatment.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Apoptosis Inducing Factor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Caspase 3; Caspase 7; Caspases; Cell Cycle; Cell Nucleus; Cysteine Proteinase Inhibitors; Cytochrome c Group; Drug Resistance, Neoplasm; Enzyme Activation; Enzyme Inhibitors; Enzyme Precursors; Flavoproteins; Gamma Rays; Humans; Jurkat Cells; Lung Neoplasms; Membrane Potentials; Membrane Proteins; Mitochondria; Poly(ADP-ribose) Polymerases; Protein Transport; Radiation Tolerance; Reactive Oxygen Species; Recombinant Fusion Proteins; Staurosporine; Superoxides; Tumor Cells, Cultured

Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Bradykinin; Carcinoma, Small Cell; Caspase 3; Caspase Inhibitors; Caspases; Cell Adhesion; Cell Division; Collagen; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Enzyme Inhibitors; Etoposide; Extracellular Matrix Proteins; Fibronectins; Galanin; Humans; Integrin beta1; Laminin; Lung Neoplasms; Protein-Tyrosine Kinases; Tenascin; Tumor Cells, Cultured; Tyrphostins