(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Carcinoma--Non-Small-Cell-Lung

Statins are commonly prescribed antilipidemic and anticholesterol class of drugs. In addition to their major role, they have been found to have anticancer effects on in vitro, animal and clinical studies. The aim of this study was to investigate the effects of six different statins (rosuvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, and atorvastatin) on A549 cancer cells lipids by Fourier transform infrared (FTIR) spectroscopy. Proliferation tests were carried out to detect the half-maximal inhibitory concentrations (IC

Topics: A549 Cells; Atorvastatin; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipids; Lovastatin; Lung Neoplasms; Pravastatin; Rosuvastatin Calcium; Simvastatin; Spectroscopy, Fourier Transform Infrared

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to overcome tyrosine kinase inhibitor (TKI) resistance in epithelial growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) cells in vivo and in vitro. However, little is known about the putative induction of non-apoptotic cell death pathways by statins. We investigated the effects of pitavastatin and fluvastatin alone or in combination with erlotinib in three NSCLC cell lines and examined the activation of different cell death pathways. We assessed apoptosis via fluorometric caspase assay and poly (ADP-ribose) polymerase 1 (PARP) cleavage. Furthermore, annexinV/propidium iodide (PI) flow cytometry was performed. Small molecule inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD), necrostatin 1 (Nec1), ferrostatin 1 (Fer1), Ac-Lys-Lys-Norleucinal (Calp1) were used to characterise cell death pathway(s) putatively (co-)activated by pitavastatin/erlotinib co-treatment. Synergism was calculated by additivity and isobolographic analyses. Pitavastatin and fluvastatin induced cell death in EGFR TKI resistant NSCLC cells lines A549, Calu6 and H1993 as shown by caspase 3 activation and PARP cleavage. Co-treatment of cells with pitavastatin and the EGFR TKI erlotinib resulted in synergistically enhanced cytotoxicity compared to pitavastatin monotherapy. Flow cytometry indicated the induction of alternative regulated cell death pathways. However, only co-treatment with mevalonic acid (Mev) or the pan-caspase inhibitor zVAD could restore cell viability. The results show that cytotoxicity mediated by statin/erlotinib co-treatment is synergistic and can overcome erlotinib resistance in K-ras mutated NSCLC and relies only on apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Erlotinib Hydrochloride; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung Neoplasms; Quinolines

Topics: Acyl Coenzyme A; Adult; Aged; Animals; Apoptosis; Carcinogenesis; Carcinogens; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Fluvastatin; Gene Knockdown Techniques; HEK293 Cells; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung; Lung Neoplasms; Male; Mevalonic Acid; Mice; Middle Aged; Neoplasms, Experimental; Nitrosamines; RNA, Small Interfering; Xenograft Model Antitumor Assays

Fluvastatin reduces tumor proliferation and increased apoptotic activity in various cancers. Special AT-rich sequence binding protein 1 (SATB1) is a genome organizer that reprogrammes the gene transcription profiles of tumors to promote growth and metastasis. The antitumor effect and molecular mechanisms of fluvastatin on lung cancer is poorly understood. This study aimed to investigate the antitumor effect of fluvastatin on lung cancer and its possible mechanics.. Cell viability assay was used to examine the inhibition of fluvastatin on proliferation of H292 cells. In order to investigate the antitumor mechanics, SATB1 knock-down H292 cells was constructed by lentiviral transfection. RT-PCR and Western blot were performed to examine the effects of fluvastatin on expression of SATB1 and Wnt/β-catenin signaling components.. Fluvastatin significantly inhibited proliferation and invasion of H292 cells in a time- and dose-dependent manner and promoted the apoptosis (p < 0.05). The expression of SATB1 was down-regulated by fluvastatin in a dose-dependent manner. The proliferation and invasion of SATB1-shRNA cells was significantly suppressed, and the apoptosis was significantly enhanced (p < 0.05). We also show that the common target genes were regulated by SATB1 and Wnt/β-catenin pathway simultaneously. There may be a functional link between SATB1 and Wnt/β-catenin pathway.. We presented a possible mechanism of statins that fluvastatin significantly suppressed the in vitro tumor progression of H292 cells possibly by down-regulation of SATB1 via Wnt/β-catenin pathway, which provided new therapeutic possibilities for more cancers driven by hyperexpression of SATB1 and Wnt/β-catenin pathway.

Topics: A549 Cells; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Down-Regulation; Fluvastatin; Humans; Lung Neoplasms; Matrix Attachment Region Binding Proteins; Neoplasm Invasiveness; Phenotype