The effect of combined treatment with sodium phenylbutyrate and cisplatin, erlotinib, or gefitinib on resistant NSCLC cells

Abstract

Maha S Al-Keilani,1 Karem H Alzoubi,1 Saied A Jaradat2,3 1Department of Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan; 3Princess Haya Center for Biotechnology, Jordan University of Science and Technology, Irbid 22110, Jordan Background: Chemotherapy resistance is the main cause of the marginal clinical benefit of platinum-based chemotherapy and tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC). Thus, the identification of new therapeutic agents that can enhance the sensitivity of these drugs is of clinical importance. Histone deacetylase inhibitors (HDACIs) are emerging as new promising agents with strong antiproliferative effects against different types of cancers. This study investigates the synergistic potential of sodium phenylbutyrate (NaPB) added on top of standard chemotherapy used against NSCLC. Objective: The objective of this study was to evaluate the ability of NaPB to overcome the resistance of NSCLC cell lines to cisplatin, gefitinib, and erlotinib. Methods: MTT cell proliferation assay was used to measure the anticancer effects of cisplatin, erlotinib, or gefitinib alone or combined with various concentrations of NaPB against A549, Calu1, and H1650 NSCLC cell lines. Synergism was estimated by measuring synergy value (R), which is equal to the ratio of IC50 of each primary drug alone divided by combination IC50s. Student’s t-test analysis was used to evaluate the potential differences between IC50 values. ANOVA followed by Tukey’s post hoc was used to evaluate the potential differences among monotherapy and combination treatment groups. Analyses were performed using R 3.3.2 software. P-value <0.05 was considered to be statistically significant. Results: NaPB was shown to inhibit the growth of A549, Calu1, and H1650 cell lines in a dose-dependent manner (IC50 10, 8.53, and 4.53 mM, respectively). Furthermore, the addition of NaPB along with cisplatin, erlotinib, or gefitinib to A549, Calu1, and H1650 cell lines resulted in a synergistic antiproliferative effect against the three NSCLC cell lines (R>1.6, P-value <0.05), thus suggesting that NaPB can potentiate the effect of cisplatin, erlotinib, and gefitinib on A549, Calu1, and H1650 cell lines. Conclusion: Current results suggest a potential role of NaPB as a sensitizing agent in NSCLC. Keywords: NSCLC, resistance, histone deacetylase inhibitor, sodium phenylbutyrate, synergism, sensitizing chemotherap