Cancer and many other diseases require concomitant treatments with combinations of many drugs.Debrisoquine 4-Hydroxylayase (CYP2D6) is microsomal enzyme involved in phase I metabolism of a long list of drugs. Also, it is a marker of inter-individual variability in drug responsiveness. This study was designated to explore the regulation of CYP2D6 in hepatoma cells exposed to combinations of anticancer and epigenetic modifying drugs. HepG2 cell were treated with combinations of anticancer drug (Taxol), glucocorticoid (dexamethasone, DEX) and epigenetic modifiers: Trichostatin A (TSA) and 5 aza-deoxycytidine (5 aza-dC). The expression of CYP2D6 was determined by quantitative RT-PCR and compared to other CYPs and the corresponding cumulative apoptotic effect was determined by flow cytometry. The obtained results revealed thatUnder non-induced conditions, CYP2D6 was stably expressed and sub micromolar concentration of DEX mildly increased its expression. Individual treatments as DEX, Taxol, TSA and 5-azadC induced 2-6-fold increase in the transcript level, where the TSA was the most potent inducer. Combinations of 2 drugs as (Taxol+DEX), (Taxol+TSA), (Taxol+5-aza-dC) and (TSA+5-aza-dC). led to 3-10-fold increase (average 6.2), whereas cocktails of 3 drugs as (Taxol+DEX+5-aza-dC), (Taxol+DEX+TSA) and (Taxol+TSA+5-aza-dC) led to further up regulatory effect (11-27-fold). The highest increment (28-fold) was observed when cells were treated with 4 drugs as (Taxol+TSA+5-aza-dC+DEX). The progressive induction of CYP2D6 was correlated with the cumulative apoptotic effect (r=0.79). Conclusively, the data suggest, for the first time, that anticancer, epigenetic regulatory factors and dexamethasone cumulatively enhanced the baseline expression of CYP2D6