Epigenetic sensitization of non-small cell lung cancer to 5-Fluorouracil


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Israa Al-Humairi1
1University of LIverpool

Abstract

Background

Lung cancer is the leading cause of cancer related death worldwide and it is desirable to find more effective therapeutic strategy for lung cancer patients. 5- Fluorouracil is one of the most widely used chemotherapeutic agents for several types of cancers; however, resistance is one of the major obstacles for successful treatment. Using the two well known epigenetic modifiers, methyltransferase (DNMT) inhibitor Decitabine and histone deacetylase (HDAC) class I inhibitor Valproic acid (VPA), we investigated the possibility of reversing 5-FU resistance by epigenetically sensitizing the most resistance NSCLC cell lines with the highest 5-FU IC50 value A549 and SK-MES-1.

Method

MTT assay was used to assess the growth inhibitory effect of all compounds used in this study. Thymidylate synthase (TYMS) mRNA expression was performed using Taqman-based qPCR.

Results

Our results showed that combined treatment of 5-FU and decitabine didn’t enhance the cells sensitivity to 5-FU. Conversely, when VPA was used to treat the cells for 48 hours prior to 5-FU addition, a significant increase in 5-FU cytotoxicity was observed in the subsequent 72 hours. Interestingly, TYMS expression was significantly reduced by VPA treatment.

Conclusion

VPA augments the antitumor effect of 5-FU, therefore, combination therapy of 5-FU plus VPA might be a promising therapeutic option for NSCLC patients.

The study was supported by MOHESR/IRAQ and the Roy Castle Lung Cancer Foundation.