DNA methyltransferase inhibitors improve the effect of chemotherapeutic agents in SW48 and HT-29 colorectal cancer cells
Authors: Agnieszka Gnyszka
Krzysztof Flis
Sylwia Flis
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: DNA methylation; DNMT1; DNMT inhibitors; colorectal cancer; epigenetic modifications
Affiliations: Department of Pharmacology, National Medicines Institute, Warsaw, Poland., Department of Genetics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

Abstract:  DNA methylation is an epigenetic phenomenon known to play an important role in the development and progression of human cancer. Enzyme responsible for this process is DNA methyltransferase 1 (DNMT1) that maintains an altered methylation pattern by copying it from parent to daughter DNA strands after replication. Aberrant methylation of the promoter regions of genes critical for normal cellular functions is potentially reversible. Therefore, inactivation of DNMT1 seems to be a valuable target for the development of cancer therapies. Currently, the most popular DNMT inhibitors (DNMTi) are cytidine analogues like 5-azacytidine, 5-aza-2'-deoxycytidine (decitabine) and pyrimidin-2-one ribonucleoside (zebularine). In colorectal cancer, epigenetic modifications play an essential role at each step of carcinogenesis. Therefore, we have addressed the hypothesis that DNA methyltransferase inhibitors may potentiate inhibitory effects of classical chemotherapeutic agents, such as oxaliplatin and 5-fluorouracil (5-FU), commonly used in colorectal cancer therapy. Here, our report shows that DNMTi can have positive interactions with standard chemotherapeutics in colorectal cancer treatment. Using pharmacological models for the drug-drug interaction analysis, we have revealed that the combination of decitabine with 5-FU or oxaliplatin shows the most attractive interaction (synergism), whereas the effect of zebularine in combinations with chemotherapeutics is moderate and may be depended on genetic/epigenetic background of a cell line or secondary drug used in combination. Our results suggest that DNMTi administered in combination with standard chemotherapeutics might improve the treatment of patients with colorectal cancers. 

Retracted: No

PubPeer comments:
 August 2014 correction as found here: https: journals.plos.org plosone article?id=10.1371 journal.pone.0106142 , which reads:  *The authors are issuing this Correction to address concerns about Figure 4B of this article. Lanes 1, 2, 4, and 5 of SW48 as well as HT-29 represent molecular weight marker and mRNA levels of particular genes in mock-, DAC- and ZEB-treated cells, respectively. The experimental conditions for each cell line presented in Figure 4B were tested in the same experiment, therefore the lanes are the controls for both OXA- (left panel) and 5-FU-containing (right panel) conditions. Since the authors wanted to keep the same order of the samples as in Figure 4C to easily compare the effects of OXA and 5-FU and their combinations with DNMTi, the lanes 1, 2, 4, and 5 of both cell lines have been reused in the right panel; which was further a source of some concerns. Additionally, it was found that panel for the loading control (GAPDH) in Figure 4B was inadvertently duplicated, probably during figure preparation. The authors apologize for the inaccuracies in the presentation of Figure 4B. They have prepared a new Figure 4B preserving the original order of the samples and avoiding duplications and errors. The authors have also provided the original uncropped pictures of ethidium bromide agarose gels scanned from their laboratory notebooks. The results and conclusions are not affected by this correction.* Here is the original Figure 4B, with boxes of the same color showing lanes that looked identical: ![file] ,