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OBJECTIVE Gambogic acid (GA) has been approved by the Chinese Food and Drug Administration for the treatment of lung cancer in clinical trials.However, whether GA has chemosensitizing properties when combined with chemotherapy agents in the treatment of lung cancer is still unknown.Here we investigated the effects of GA combined with adriamycin (ADM), a common chemotherapy agent, in regard to their activities against lung cancer in vitro and in vivo and explored the mechanisms possibly involved.METHODS The synergistic effects of GA combined with ADM was detected by MTT and analyzed by Calcusyn 2.0 software.Flow cytometry was used to examine the cell apoptosis inducing by GA, ADM or combined treatment.The effects of GA and ADM on apoptosis-related proteins and NF-κB signaling were determined by Western blot method.Using A549 xenograft tumor model, we evaluated the antitumor activity of GA in combination with ADM in vivo.RESULTS When GA combined with ADM, it displayed synergistic cytotoxicity for lung cancer cells and enhanced apoptosis inducing action.In addition, we found that GA in combination with ADM could promote PARP cleavage and enhance Caspase-3 activation in A549 cells.Interestingly, ADM single treatment could activate NF-κB signaling in A549 ceils, but the response could be reversed by treating with GA previously.Importantly, we found that the combination of GA and ADM exerted increased anti-tumor efficacy on A549 xenograft models.CONCLUSION These findings suggest that GA sensitizes lung cancer to ADM in vitro and in vivo most likely via an inhibition of ADM induced chemoresistance involving NF-κB signaling.