Plumbagin induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human melanoma A375.S2 cells.
This study is the first to investigate the anticancer effect of plumbagin in human melanoma A375.S2 cells. Plumbagin exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Further investigation revealed that plumbagin's inhibition of cell growth was also evident in a nude mice model. Blockade of cell cycle was associated with increased levels of p21, and reduced amounts of cyclin B1, cyclin A, Cdc2, and Cdc25C. Plumbagin also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. Plumbagin triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in caspase-9 activation. We also found the generation of ROS is a critical mediator in plumbagin-induced cell growth inhibition. Plumbagin increased the activation of apoptosis signal-regulating kinase 1, JNK and extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38. In addition, antioxidants vitamin C and catalase significantly decreased plumbagin-mediated c-Jun N-terminal kinase (JNK) activation and apoptosis. Moreover, blocking ERK and JNK by specific inhibitors suppressed plumbagin-triggered mitochondrial apoptotic pathway. Taken together, these results imply a critical role for ROS and JNK in the plumbagin's anticancer activity.
Wang
Clay C C
CC
.; Department of Chemistry, University of Southern California, College of Letters, Arts, and Sciences, University Park Campus, Los Angeles, CA 90089, USA.
Chiang
Yi-Ming
YM
Sung
Shu-Chiao
SC
Hsu
Ya-Ling
YL
Chang
Jiunn-Kae
JK
Kuo
Po-Lin
PL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D005978:Glutathione; C014758:plumbagin