Inhibitory effects of single predicted drugs on colon cancer and breast cancer cell lines.

<p>–: not detected from 0.1 to 30 µM.</p

Function-drug association map (FDAM) for colorectal adenoma.

<p>Nodes in the map are functional modules (FMs; gene sets) and drugs obtained by querying CMap using individual FMs. Drug-function links indicate beneficial (green) or harmful (red). Only drugs beneficial to at least one FM are included.</p

Enrichment score versus fold-change for CMap drugs.

<p>Enrichment score (ES) was obtained by querying the CMap with gene set (size indicated by vertical bar) determined using varying fold-change (FC) threshold. A drug is considered beneficial for the treatment for colorectal adenoma if ES <−0.5, harmful if ES >0.3, and neutral otherwise. (A) Screening by IGCM procedure. Querying gene set was complete set of differentially expressed genes (DEGs) identified from gene expression arrays of colorectal adenoma cohort (versus control) using the SAM algorithm with fixed FDR <0.01. (B) Screening by FMCM procedure. Querying gene sets were functional modules obtained by partition of over-represented Gene Ontology terms in GSToP filtered DEGs.</p

Function-function networks for colorectal adenoma.

<p>Condition specific function-function networks (FFNs) were generated from gene-gene networks (GGINs), shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086299#pone.0086299.s002" target="_blank">Figure S2</a>, by reduction. Nodes in an FFN are functional modules (FMs), which are gene sets in the corresponding GGIN forming over-represented Gene Ontology terms. FMs containing less than 70 genes are not shown. The diameter of a node scales with the logarithm of the number of genes in the node. The color shade of a node indicates the number of intra-node gene-gene interactions per gene. The thickness of the edge indicates the number of inter-node gene-gene interactions.</p

Overlap of candidate repurposed drug sets curated from colon adenoma and colorectal cancer data sets.

<p>Numbers in brackets correspond to those given in the first column of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086299#pone-0086299-t001" target="_blank">Table 1</a>, which lists the drug set for colon adenoma. The overlap includes 9 of the 13 drugs in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086299#pone-0086299-t001" target="_blank">Table 1</a> with degrees not less than 3, and 5 of the 8 drugs selected for cell viability tests marked by “*”.</p

Viability test of colon and breast cancer cells treated with single drug.

<p>Tests were conducted on eight drugs: phenoxybenzamine (PB), GW-8510, phthalylsulfathiazole (PS), etacrynic acid (EA), ginkgolide A (GA), triflusal (TF), imipenem (IM), and 6-azathymine (6-AT), with concentrations of 0, 0.1, 1, 10, and 30 µM. (A) Viability of MCF7 on treatment of the eight drugs. (B) Viability of five cell lines on treatment of GW-8510. Colon cancer cells HCT116, RKO, SW403 and SW620, and the breast cancer cell MCF7, were treated with single drug for 5 days. After 5 days, proliferation activities of these cells were detected by Alamar Blue assay.</p

Predicted drug compounds for colorectal cancer adenoma.

<p>The eight GO terms (biological function classifications) included are APO, CC, CP, ST, TR, DR, CP, RM and ISP (see abbreviations below). All drugs in the table have ES (enrichment score) <−0.75 (with only one exception). None of the drugs have harmful effects (ES >0) on any of the GO functions. Only compounds with up to 6 components are given. Abbreviations: ISP: immune system process – trifusal or morantel or gingolide or cetirizine or imipenem; APO: apoptosis – irinotecan or doxazosin or cycloserine or repaglinide; CC: cell cycle – doxorubicin or withaferin A; ST: signal transduction – 6-azathymine or tyloxapol; TR: transcription – sanguinarine; DR: DNA replication – piperlongumine; CP: Cell proliferation – bepridil; RM: RNA metabolic process – skimmianine; TDNA: transcription and DNA replication –chrysin or thioguanosine or luteolin or thiostrepton or sulconazole. The “degrees” in “Ratio of degrees” indicate the number of functional modules to which the corresponding component is beneficial.</p

Clustering of genomic profiles of drug-treated cancer cell lines HCT116 and MCF7.

<p>(A) Individual gene approach (IGA). (B) Gene-set approach (GSA). Cell lines were treated with three drugs: GW-8510, phenoxybenzamine (PB), and imipenem. Entries marked “cmap” were microarray drug treatment genomic profiles of MCF7 taken from the CMap. Others were from drug treatment microarray experiments (Affymetrix U219 (PrimeView) platform) conducted for the present study, where the same experimental protocol used in CMap were followed: averaged over three dosages of 10 M, 11.8 M, 13.4 M; treatment time 6 hours after overnight culture. Heatmaps were results of two-way hierarchical clustering.</p