title: Synergistic action by multi-targeting compounds produces a potent compound combination for human NSCLC both in vitro and in vivo.
abstract: By screening a collection of one hundred combinations of thiazolidinone compounds, we identified one combination (M4) that synergistically inhibited the growth of H460 and H460/TaxR cells and tumor growth in H460/TaxR xenograft mice. A whole genome microarray assay showed that genes involved in negative regulation of microtubule polymerization or depolymerization, intracellular protein kinase cascade, positive regulation of histone acetylation, cell cycle arrest and apoptosis were upregulated. Further analysis proved that the four compounds act as either microtubule polymerization inhibitors or histone deacetylase inhibitors. They act synergistically targeting multiple proteins and leading to the regulation of cell cycle checkpoint proteins, including p53, p21, cdc25C and cdc2, the activation of caspases, JNK, p38 cascades and the inactivation of Akt. These events resulted in the G2/M cell cycle arrest and cell apoptosis. These data provide a new strategy for discovering anticancer drugs and drug combinations for drug-resistant cancers.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhai
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: C
authors.initials: C
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: G
authors.initials: G
authors.lastname: Su
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
authors.forename: B
authors.initials: B
authors.lastname: Yan
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D053778:Thiazolidines; D050257:Tubulin Modulators