pf-477736 and Carcinoma--Non-Small-Cell-Lung

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzodiazepinones; Biomarkers, Tumor; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Deoxycytidine; Drug Resistance, Neoplasm; Drug Synergism; Female; Gemcitabine; Humans; Mice; Mice, Nude; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Pyrazoles; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Spheroids, Cellular; Tumor Cells, Cultured