Pharmacogenomic identification of c-Myc/Max-regulated genes associated with cytotoxicity of artesunate towards human colon, ovarian and lung cancer cell lines.

Details

Serval ID
serval:BIB_2EC9B3234E07
Type
Article: article from journal or magazin.
Collection
Publications
Title
Pharmacogenomic identification of c-Myc/Max-regulated genes associated with cytotoxicity of artesunate towards human colon, ovarian and lung cancer cell lines.
Journal
Molecules
Author(s)
Sertel S., Eichhorn T., Simon C.H., Plinkert P.K., Johnson S.W., Efferth T.
ISSN
1420-3049 (Electronic)
ISSN-L
1420-3049
Publication state
Published
Issued date
2010
Volume
15
Number
4
Pages
2886-2910
Language
english
Notes
Publication types: Journal ArticlePublication Status: epublish
Abstract
Development of novel therapy strategies is one of the major pressing topics of clinical oncology to overcome drug resistance of tumors. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We applied a gene-hunting approach using microarray-based transcriptome-wide mRNA expression profiling and COMPARE analyses. We identified a set of genes, whose expression was associated either with high IC50 values or low IC50 values for ART. Therefore, these genes may function as resistance or sensitivity factors for response of tumor cells towards ART. This viewpoint is conceivable for genes involved in ribosomal activity, drug transport, cellular antioxidant defense, apoptosis, cell proliferation, cell cycle progression etc. An investigation of underlying signal transduction by pathway analysis suggested a role of the signaling pathways related to tumor necrosis factor (TNF) and the tumor suppressor p53. On the other hand, there were genes without obvious functional link to cellular response to ART, such as genes involved in the survival of cochlear outer and inner hair cells etc. We proved the hypothesis that ART influences the activity of transcription factors regulating downstream genes involved or not involved in response of cancer cells towards ART. This would explain the identification of genes with and without obvious relation to the cytotoxic activity of ART by microarray and COMPARE analyses. By analysis of the binding motifs for the transcription factors c-Myc and Max, we indeed found that 53 of 56 genes contained one or more binding sites for c-Myc/Max upstream of the gene-location. We conclude that c-Myc and Max-mediated transcriptional control of gene expression might contribute to the therapeutic effects of ART in cancer cells, but may also confer unwanted side effects by affecting therapy-unrelated genes.
Keywords
Artemisinins/pharmacology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism, Cell Line, Tumor, Colonic Neoplasms/genetics, Drug Resistance, Neoplasm/genetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Humans, Inhibitory Concentration 50, Lung Neoplasms/genetics, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms/genetics, Pharmacogenetics, Proto-Oncogene Proteins c-myc/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
21/01/2013 15:06
Last modification date
20/08/2019 13:13
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