Pharmacogenomic Identification of c-Myc/Max-Regulated Genes Associated with Cytotoxicity of Artesunate towards Human Colon, Ovarian and Lung Cancer Cell Lines

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.

Anticancer Properties of Distinct Antimalarial Drug Classes

“…As expected, regulatory genes involved in signal transduction, transcription and apoptosis were prominent but, given that different gene sets associated with the compounds, remarkably similar; presumably, different genes associated with the various compounds were binned in the same category, resulting in the apparent convergence when results are displayed in this “high-level” format. Previously, a similar study to ours was performed with artesunate, but using a different cell line panel and microarray platform [85]. Interestingly, the top-ranked “resistance” gene in that study, SLC30A1, was also assigned by us as such (Data S1), and we found that expression of this gene was only significantly associated with ART (p = 0.0026), not the other compounds, emphasizing the unique character of each compound that we tested.…”

Annual Wormwood Leaf Inhibits the Adipogenesis of 3T3-L1 and Obesity in High-Fat Diet-Induced Obese Rats

“…For example, it can exhibit anti-proliferative effects or induce apoptosis in various tumour cell lines in vitro and in vivo [21,22]. Additionally, Artemisia annua L. (AWL) has demonstrated significant anti-oxidant, anti-inflammatory, and anti-microbial properties [12].…”

Evaluation of the antitumor effects of c-Myc-Max heterodimerization inhibitor 100258-F4 in ovarian cancer cells

“…These results clearly pose an interesting possibility: that the concurrent disruption of c-Myc-Max heterotetramerization might also interfere with target gene expression in other ways in various cell types [19,21]. This result could also account for the heterogeneity of primary cultures of ovarian cancer, showing small portions of stromal cells in some cases in our primary culture system, and this presence of stromal cells may affect the viability of and c-Myc function in the ovarian primary cultures.…”