Abstract
BackgroundDrinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out.MethodsHere we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI50 data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested in vitro for the ability to influence tumor susceptibility to arsenic trioxide.ResultsA significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down.ConclusionsIn this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.
Highlights
Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer
The NCI-60 human tumor cell panel was used in the in vitro cell line screening project (IVCLSP) under the developmental therapeutics program (DTP) program, where 59 cell lines in the NCI-60 cell panel were exposed to arsenic trioxide for 48 hours and growth inhibition of 50% (GI50) was recorded as the drug concentration resulting in a 50% reduction in the net protein increase in control cells during the drug incubation [15]
Using data obtained from the DTP database [23], it is clear that the NCI-60 human tumor cell lines show differential cytotoxicity responses upon exposure to arsenic trioxide
Summary
Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out. The first clinical trial on arsenic trioxide treatment of relapsed APL patients after resistance to all-trans-retinoic acid (ATRA) treatment was carried out in China with a complete remission rate of 72% [6]. In another NCI-sponsored cancer and leukemia study, 77% of newly diagnosed APL patients who received combined chemotherapy and single arsenic trioxide treatment remained in remission 3 years after diagnosis [7]. A comprehensive study examining the mechanisms and potential signaling pathways contributing to its anti-tumor properties has not been carried out
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