English: Cancer is being considered one of the fatal diseasesin the global population. Lung cancer is one of the most common malignancies in males and inseveral countries also in females.In the presentstudy, we aimed at evaluating the role of different chemotherapeutic drugs belonging to three groups [Histone DeacetylaseInhibitors (HDACi), DNA Methyltransferase Inhibitors (DNMTi), and Alkylating Agents)]. Vorinostat, Carboplatin, Cyclophosphamide, Temozolomide, and Procaine were applied to A549 lung cancer cells in final concentrations of 3μM and 5μM. Drugs were incubated with the cells for 96 h. Cell viability was measured using Trypan blue exclusion test, and the obtained results showed a significant decrease in the cells' viability after being treated. Global methylation, as an essential epigenetic mark, was quantified in the control and treated cells. The results showed a variation in the methylationpatterns, since different combination yielded different methylation profiles. Vorinostat combined with Carboplatinhypomethylated the cells under study, while Vorinostat combined with Cyclophosphamide resulted in hypermethylation of the cells. We concluded that reactivating thehypermethylated genes in the A549 lung cancer cells by combining more than one drug was significantly better than that induced by only one chemotherapeutic agent. However, these results need more confirmatory experiments.