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1.
Front Med ; 7(4): 462-76, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23820871

ABSTRACT

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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm , Neoplastic Stem Cells/drug effects , Spheroids, Cellular/drug effects , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzodiazepinones/administration & dosage , Biomarkers, Tumor/metabolism , Blotting, Western , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Drug Synergism , Female , Humans , Mice , Mice, Nude , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Oligonucleotide Array Sequence Analysis , Pyrazoles/administration & dosage , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Spheroids, Cellular/metabolism , Spheroids, Cellular/pathology , Tumor Cells, Cultured , Gemcitabine
2.
J Med Chem ; 50(22): 5253-6, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17887663

ABSTRACT

The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinases/metabolism , Pyrazoles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Breast Neoplasms , Cell Line, Tumor , Checkpoint Kinase 1 , Crystallography, X-Ray , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Drug Design , Drug Screening Assays, Antitumor , Drug Synergism , Female , Humans , Indazoles/chemistry , Male , Models, Molecular , Molecular Structure , Prostatic Neoplasms , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinases/chemistry , Pyrazoles/chemistry , Pyrazoles/pharmacology , Structure-Activity Relationship , Gemcitabine
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