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We have found that both studied HDACi, used in moderate doses up to 20 μM, inhibited, in a dose-dependent manner, the growth of CRC Pemetrexed when given alone and showed potent synergism with oxaliplatin (the latter used in concentrations of 2.5, 5, and 40 μM, depending on cell lines studied) as evidenced by pharmacological analysis (Fig. 2 and Table 1). The obtained combination index was in the case of OXA and MS275 between 0.21 and 0.49 and in the case of OXA and SBHA between 0.51 and 0.85, at 75% of fraction affected (Fa) level, depending on cell line (Table 1). Thus, the oxaliplatin-induced inhibition of CRC survival could be synergistically augmented, especially by MS275, at low doses of both agents.
In summary, we have demonstrated that HDAC inhibitors, especially MS275 and to a lesser degree, SBHA, exerted synergistic interaction with oxaliplatin, inhibiting the survival of CRC cells in vitro. The mechanism of synergism between evaluated agents is probably related to the augmentation of apoptotic signal, resulting from both intrinsic and extrinsic pathways probably caused, at least in part, by generation of ROS. It appeared that observed synergism between MS275 and oxaliplatin results in mutual completion and enhancement of anticancer activity that may be of importance for the clinic.