Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) suppresses NF-kappaB activation and NF-kappaB-regulated gene products through modulation of p65 and IkappaBalpha kinase activation, leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents.
Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-kappaB, suggesting plumbagin might affect the NF-kappaB activation pathway. We found that plumbagin inhibited NF-kappaB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1beta, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-kappaB activation in certain tumor cells. The suppression of NF-kappaB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-beta, and the p65 subunit of NF-kappaB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-kappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-kappaB activation pathway that leads to suppression of NF-kappaB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.
Sandur
Santosh K
SK
Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Ichikawa
Haruyo
H
Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Sethi
Gautam
G
Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Ahn
Kwang Seok
KS
Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Aggarwal
Bharat B
BB
Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030. Electronic address: aggarwal@mdanderson.org.
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation; D008956:Models, Chemical; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation; D020298:U937 Cells
D000970:Antineoplastic Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009285:Naphthoquinones; D000072000:NF-KappaB Inhibitor alpha; D004229:Dithiothreitol; C014758:plumbagin