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Purpose:A vast variety of naturally occurring substances have been shown to protect against experimental carcinogenesis and an increasing amount of evidence suggests that two plant-derived drug, triptolide (TP) from the plant Tripterygium wilfordii Hook.f.(TWHF) and hydroxycamptothecin (HCPT) from a Chinese native plant Camptotheca accuminata, may have cancer chemopreventative properties.We have recently documented that combination treatment with these two plant-derived drugs act more effective on growth inhibition of human pancreatic cancer cell line PANC-1 than each drug is used alone (SW YANG et al.,Am J Chin Med., 2011, 39:121-34).This leads to the hypothesis that these two agents TP and HCPT might act synergistically for chemotherapy.However, the molecular mechanism and possible signaling pathway still need further investigation.Experimental Design:The synergistic effects of TP and HCPT, on human lung cancer cell line A549, were examinedfor cell growth, cell morphology, cell cycle distribution, and apoptosis.Futher western blot experiments were performedto determine whether this synergistic combination oftwo drugs has significant effect on biochemical markers of apoptosis.Resuhs: After 24 h, TP and HCPT each caused a dose-dependent reduction in cell viability, respectively.Notably, theTP-HCPT combination treatmentacted more effective on growth inhibition of A549 cells than single drug alone.In addition, enhanced cell apoptosis and increasedpercentage of apoptotic Sub-G1 phase in cells treated by the combination were observed, correlated with enhanced activation of caspases 3 and 9 , elevated Bax/Bal-2 ratio and release of cytochrome c from mitochondrial, suggesting that Bax-and Bcl-2-triggered mitochondrial apoptotic pathwaymay contributeto the synergistic cytotoxic effect of this combination therapy.Conclusions: As the combination treatment of TP and HCPT causing synergistic inhibition of cancer cell growth are clinically achievable, these data providedevidence supporting the clinical applications of the combination chemotherapy with this combination.