prodigiosin and Lung-Neoplasms

Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is unclear. To date, only the inhibition of BCL-2 proteins has been proposed as a mechanism of action. To gain insight into other possible modes of action, we have studied the anion-binding properties of obatoclax and related analogues in solution, in the solid state, and by means of density functional theory calculations. These compounds are well suited to interact with anions such as chloride and bicarbonate. The anion-transport properties of the compounds synthesized were assayed in model phospholipid liposomes by using a chloride-selective-electrode technique and (13)C NMR spectroscopy. The results demonstrated that these compounds are efficient anion exchangers that promote chloride, bicarbonate, and nitrate transport through lipid bilayers at very low concentrations. In vitro studies on small-cell lung carcinoma cell line GLC4 showed that active ionophores are able to discharge pH gradients in living cells and the cytotoxicity of these compounds correlates well with ionophoric activity.

Topics: Animals; Anions; Antineoplastic Agents; Apoptosis; Biological Transport; Cattle; Cell Line, Tumor; Crystallography, X-Ray; Humans; Indoles; Ion Transport; Ionophores; Liposomes; Lung Neoplasms; Magnetic Resonance Spectroscopy; Prodigiosin; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Tumor Cells, Cultured

An entomopathogenic bacterial strain SCQ1 was isolated from silkworm (Bombyx mori) and identified as Serratia marcescens via 16S rRNA gene analysis. This strain produces a red pigment that causes acute septicemia of silkworm. The red pigment of strain SCQ1 was identified as prodigiosin analogue (PGA) with various reported biological activities. In this study, we found that low concentration of PGA showed significant anticancer activity in human lung adenocarcinoma A549 cells, but has little effect in human bone marrow stem cells, in vitro. By exposure to different concentrations of PGA for 24 h, morphological changes and the MTT assay showed that A549 cell line was very sensitive to PGA, with IC(50) value about 2.2 mg/L. Early stage of apoptosis was detected by flow cytometry while A549 cells were treated with PGA for 4 and 12 h, respectively. The proportion of dead cells was increased with treatment time or the concentrations of PGA, but it was inversely proportional to that of apoptotic cells. These results indicate that PGA obtained from strain SCQ1 induces apoptosis in A549 cells, but the molecular mechanisms of cell death are complicated, and the S. marcescens strain SCQ1 may serve as a source of the anticancer compound, PGA.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bombyx; Cell Line, Tumor; Cell Survival; Cluster Analysis; DNA, Bacterial; DNA, Ribosomal; Humans; Inhibitory Concentration 50; Lung Neoplasms; Molecular Sequence Data; Phylogeny; Prodigiosin; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Serratia marcescens; Tetrazolium Salts; Thiazoles; Time Factors

In the present study, we describe the cytotoxicity of the new drug prodigiosin (PG) in two small cell lung carcinoma (SCLC) cell lines, GLC4 and its derived doxorubicin-resistant GLC4/ADR cell line, which overexpresses multidrug-related protein 1 (MRP-1). We observed through Western blot that PG mediated cytochrome c release, caspase cascade activation and PARP cleavage, thereby leading to apoptosis in a dose-response manner. MRP-1 expression increased after PG treatment, although that does not lead to protein accumulation. The MTT assay showed no difference in sensitivity to PG between the two cell lines. Our results support PG as a potential drug for the treatment of lung cancer as it overcomes the multidrug resistance phenotype produced by MRP-1 overexpression.

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Small Cell; Caspases; Cytochromes c; Doxorubicin; Drug Resistance, Neoplasm; Enzyme Activation; Humans; Lung Neoplasms; Poly(ADP-ribose) Polymerases; Prodigiosin; Tumor Cells, Cultured

Prodigiosin (PG) is a secondary metabolite, isolated from a culture of Serratia marcescens, which has shown potent cytotoxicity against various human cancer cell lines as well as immunosuppressive activity. The purpose of this study was to evaluate the role of mitochondria in PG-induced apoptosis. Therefore, we evaluated the apoptotic action of PG in GLC4 small cell lung cancer cell line by Hoechst 33342 staining. In these cells, we examined mitochondrial apoptosis-inducing factor (AIF) and cytochrome c (cyt c) release to the cytosol in PG time-response studies. These findings suggest that PG induces apoptosis in both caspase-dependent and caspase-independent pathways.

Topics: Apoptosis; Carcinoma, Small Cell; Cell Line, Tumor; Cytochromes c; Humans; Lung Neoplasms; Microscopy, Fluorescence; Mitochondria; Prodigiosin