MicroRNAs are strongly implicated in such processes as development, carcinogenesis, cell survival, and apoptosis. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. In the experimental system, we increased the expression of individual microRNAs by transfecting their precursors (which are active) or suppressed the expression by transfection of antisense oligomers. In three NCI-60 human cancer cell lines, a panel of 60 lines used for anticancer drug discovery, we assessed the growthinhibitory potencies of 14 structurally diverse compounds with known anticancer activities. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growthinhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that f30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Ten of those microRNAs have already been implicated in cancer biology. Our results support a substantial role for microRNAs in anticancer drug response, suggesting novel potential approaches to the improvement of chemotherapy. [Mol Cancer Ther 2008;7(1):1 -9]
Advances in the understanding of cancer cell biology and response to drug treatment have benefited from new molecular technologies and methods for integrating information from multiple sources. The NCI-60, a panel of 60 diverse human cancer cell lines, has been used by the National Cancer Institute to screen >100,000 chemical compounds and natural product extracts for anticancer activity. The NCI-60 has also been profiled for mRNA and protein expression, mutational status, chromosomal aberrations, and DNA copy number, generating an unparalleled public resource for integrated chemogenomic studies. Recently, microRNAs have been shown to target particular sets of mRNAs, thereby preventing translation or accelerating mRNA turnover. To complement the existing NCI-60 data sets, we have measured expression levels of microRNAs in the NCI-60 and incorporated the resulting data into the CellMiner program package for integrative analysis.
Modern approaches to drug discovery have dramatically increased the speed and quantity of compounds that are made and tested for potential potency. The task of collecting, organizing, and assimilating this information is a major bottleneck in the discovery of new drugs. We have developed LeadScope a novel, interactive computer program for visualizing, browsing, and interpreting chemical and biological screening data that can assist pharmaceutical scientists in finding promising drug candidates. The software organizes the chemical data by structural features familiar to medicinal chemists. Graphs are used to summarize the data, and structural classes are highlighted that are statistically correlated with biological activity.
Genomic studies are producing large databases of molecular information on cancers and other cell and tissue types. Hence, we have the opportunity to link these accumulating data to the drug discovery processes. Our previous efforts at 'information-intensive' molecular pharmacology have focused on the relationship between patterns of gene expression and patterns of drug activity. In the present study, we take the process a step further-relating gene expression patterns, not just to the drugs as entities, but to approximately 27,000 substructures and other chemical features within the drugs. This coupling of genomic information with structure-based data mining can be used to identify classes of compounds for which detailed experimental structure-activity studies may be fruitful. Using a systematic substructure analysis coupled with statistical correlations of compound activity with differential gene expression, we have identified two subclasses of quinones whose patterns of activity in the National Cancer Institute's 60-cell line screening panel (NCI-60) correlate strongly with the expression patterns of particular genes: (i) The growth inhibitory patterns of an electron-withdrawing subclass of benzodithiophenedione-containing compounds over the NCI-60 are highly correlated with the expression patterns of Rab7 and other melanoma-specific genes; (ii) the inhibitory patterns of indolonaphthoquinone-containing compounds are highly correlated with the expression patterns of the hematopoietic lineage-specific gene HS1 and other leukemia genes. As illustrated by these proof-of-principle examples, we introduce here a set of conceptual tools and fluent computational methods for projecting directly from gene expression patterns to drug substructures and vice versa. The analysis is presented in terms of the NCI-60 cell lines and microarray-based gene expression patterns, but the concept and methods are broadly applicable to other large-scale pharmacogenomic database sets as well. The approach (SAT for Structure-Activity-Target) provides a systematic way to mine databases for the design of further structure-activity studies, particularly to aid in target and lead identification.
Statistical data mining methods have proven to be powerful tools for investigating correlations between molecular structure and biological activity. Recursive partitioning (RP), in particular, offers several advantages in mining large, diverse data sets resulting from high throughput screening. When used with binary molecular descriptors, the standard implementation of RP splits on single descriptors. We use simulated annealing (SA) to find combinations of molecular descriptors whose simultaneous presence best separates off the most active, chemically similar group of compounds. The search is incorporated into a recursive partitioning design to produce a regression tree for biological activity on the space of structural fingerprints. Each node is characterized by a specific combination of structural features, and the terminal nodes with high average activities correspond, roughly, to different classes of compounds. Using LeadScope structural features as descriptors to mine a database from the National Cancer Institute, the merging of RP and SA consistently identifies structurally homogeneous classes of highly potent anticancer agents.
To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI-National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations-indicative of MDR1-mediated resistance-were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.
Glutathione detoxification has been broadly implicated in resistance to chemotherapy. This study explores the relationship between chemical structure and GSH-mediated chemoresistance. System xc-, the heterodimeric cystine/glutamate exchanger composed of SLC7A11 and SLC3A2, plays a role in maintaining cellular glutathione (GSH) levels. Previous results show that SLC7A11 expression negatively correlates with drug potency across the National Cancer Institute's 60 cell lines for compounds susceptible to GSH-mediated chemoresistance. The number of significant SLC7A11-drug correlations was much greater than those of other genes tested, suggesting that SLC7A11 plays a critical role. Approximately 15% of a curated set of 3045 compounds yielded significant negative SLC7A11 correlations. These compounds tend to contain structural features amenable to GSH reactivity, such as Mannich bases. In cell lines strongly expressing SLC7A11, the potency of selected compounds, was enhanced by inhibition of SLC7A11. This system provides a rapid screen for detecting susceptibility of anticancer drugs to GSH-mediated resistance.
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