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.