Unknown,Transcriptomics,Genomics,Proteomics

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Differential gene expression for A2780 human ovarian cancer cells when exposed to a new osmium-based anticancer agent

ABSTRACT: Platinum-based metallodrugs are the most widely used anticancer agents. Their reduced effectiveness after repeat dosing (resistance) constitutes a major clinical problem. In this experiment we study a potent organo-osmium compound with improved activity over cisplatin and no cross-resistance in platinum-resistant cancers. A2780 cells were exposed to an osmium anticancer compound and to a negative control solution, in triplicate. At 0, 4, 12, 24 and 48 h, cells were collected for each condition, and whole cell RNA was extracted. Samples were purified and QC checked before Truseq library preparation and Illumina sequencing. Each sample had approximately 30 million paired-end reads. Samples were mapped to the human genome using Tophat2 and differential expression analysed using edgeR.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Peter Sadler

PROVIDER: E-MTAB-2758 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells.

Hearn Jessica M JM Romero-Canelón Isolda I Munro Alison F AF Fu Ying Y Pizarro Ana M AM Garnett Mathew J MJ McDermott Ultan U Carragher Neil O NO Sadler Peter J PJ

Proceedings of the National Academy of Sciences of the United States of America 20150710 29

The organometallic "half-sandwich" compound [Os(η(6)-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NAD ...[more]

PMID: 26162681

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Project description:In this study, the researchers isolated a colorless waxy solid from the chloroform extract of Allium stipitatum as Compound 1. They demonstrated compound 1 is a potent bactericidal agent against nonreplicating Mycobacterium tuberculosis. Using microarray technology the authors report gene expression profiles in cells treated with either 2, 5, or 10 ug/ml of compound 1 or an equivalent amount of DMSO as control for 6 h. Gene expression studies revealed that transcriptional profiles elicited in response to compound 1 were similar to the profiles generated during treatment of cells with compounds such as menadione and 8-quinolinol that result in oxidative stress. They included the thioredoxin system components encoded by trxB2 and trxC as well as several genes associated with the heat shock response such as clpB, sigH, dnaJ, dnaK, hsp, Rv0331, Rv3463, Rv3054c, and Rv1334-Rv1335. These results suggest that compound 1 possibly generates damaged proteins and other oxidative stress signals as part of its mechanism of action. The following is the full abstract of this published study. O'Donnell G, et al. (2009) J Nat Prod 72(3):360-365 From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2'-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide. Compounds 1 and 2 are new natural products, and 3 is reported for the first time from an Allium species. All compounds were evaluated for activity against fast-growing species of Mycobacterium, methicillin-resistant Staphylococcus aureus, and a multidrug-resistant (MDR) variants of S. aureus. Compounds 1 and 2 exhibited minimum inhibitory concentrations (MICs) of 0.5-8 mug/ml against these strains. A small series of analogues of 1 were synthesized in an attempt to optimize antibacterial activity, although the natural product had the most potent in vitro activity. In a whole-cell assay at 30 mug/ml, 1 was shown to give complete inhibition of the incorporation of (14)C-labeled acetate into soluble fatty acids, indicating that it is potentially an inhibitor of fatty acid biosynthesis. In a human cancer cell line antiproliferative assay, 1 and 2 displayed IC(50) values ranging from 0.3 to 1.8 muM with a selectivity index of 2.3 when compared to a human somatic cell line. Compound 1 was evaluated in a microarray analysis that indicated a similar mode of action to menadione and 8-quinolinol by interfering with the thioredoxin system and up-regulating the production of various heat shock proteins. This compound was also assessed in a mouse model for in vivo toxicity. A dose response design type examines the relationship between the size of the administered dose and the extent of the response of the organism(s). Compound Based Treatment: Allium stipitatum (garlic) extract dose_response_design

Dataset Information

Differential gene expression for A2780 human ovarian cancer cells when exposed to a new osmium-based anticancer agent

Publications

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells.

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