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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Plumbagin (5-Hydroxy-2-methyl-1,4-naphthoquinone) Induces Apoptosis and Cell Cycle Arrest in A549 Cells through p53 Accumulation via c-Jun NH₂-Terminal Kinase-Mediated Phosphorylation at Serine 15 in Vitro and in Vivo

Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan (Y.-L.H., P.-L.K., Y.-T.H.); and Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (C.-Y.C., C.-C.L.)

This study first investigates the anticancer effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) in human nonsmall cell lung cancer cells, A549. Plumbagin has exhibited effective cell growth inhibition by inducing cancer cells to undergo G₂/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21 and reduced amounts of cyclinB1, Cdc2, and Cdc25C. Plumbagin treatment also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. Blockade of p53 activity by dominant-negative p53 transfection partially decreased plumbagin-induced apoptosis and G₂/M arrest, suggesting it might be operated by p53-dependent and independent pathway. Plumbagin treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that c-Jun NH₂-terminal kinase (JNK) is a critical mediator in plumbagin-induced cell growth inhibition. Activation of JNK by plumbagin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and MDM2 interaction. SP600125 (anthra [1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone), a specific inhibitor of JNK, significantly decreased apoptosis by inhibiting the phosphorylation of p53 (serine 15) and subsequently increased the interaction of p53 and MDM2. SP6000125 also inhibited the phosphorylation of Bcl-2 (Ser70) induced by plumbagin. Further investigation revealed that plumbagin's inhibition of cell growth effect was also evident in a nude mice model. Taken together, these results suggest a critical role for JNK and p53 in plumbagin-induced G₂/M arrest and apoptosis of human nonsmall cell lung cancer cells.

Address correspondence to: Dr. Chun-Ching Lin, Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan. E-mail: aalin{at}ms24.hinet.net

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