With conventional anticancer agents for non-small cell lung cancer (NSCLC) reaching therapeutic ceiling, the novel combination using histone deacetylase inhibitor, PXD101 (Belinostat((R))), and CDK inhibitor, CYC202 (Seliciclib((R))), was investigated as an alternative anticancer strategy. At clinically achievable concentration of CYC202 (15 microM), combination therapy resulted in significant reduction in cell proliferation (IC50 = 3.67 +/- 0.80 microM, p < 0.05) compared with PXD101 alone (IC50 = 6.56 +/- 0.42 microM) in p53 wild-type A549 cells. Significant increase in apoptosis that occurred independently of cell cycle arrest was observed after concurrent treatment. This result was corroborated by greater formation of cleaved caspase-8, caspase-3 and PARP. Up-regulation of p53 and truncated BID protein levels was seen while Mcl-1 and XIAP protein levels were down-regulated upon combined treatment. Further analysis of apoptotic pathways revealed that caspase inhibitors, but not p53 silencing, significantly abrogated the cytotoxic enhancement. Moreover, the enhanced efficacy of this combination was additionally confirmed in p53 null H2444 cells, suggesting the potential of this combination for treatment of NSCLC that are not amenable to effects of conventional p53-inducing agents.