title: Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), isolated from Plumbago zeylanica, inhibits ultraviolet radiation-induced development of squamous cell carcinomas.
abstract: Plumbagin (PL) (5-hydroxy-2-methyl-1,4-napthoquinone), a medicinal plant-derived naphthoquinone, was isolated from the roots of the Plumbago zeylanica L. (also known as Chitrak). The roots of P. zeylanica L. have been used in Indian medicine for >2500 years as an anti-atherogenic, cardiotonic, hepatoprotective and neuroprotective agent. We present here that topical application of non-toxic doses (100-500 nmol) of PL to skin elicits dose-dependent inhibition of ultraviolet radiation (UVR)-induced development of squamous cell carcinomas (SCC). In this experiment, FVB/N mice were exposed to UVR (2 kJ/m(2)) three times weekly from a bank of six Kodacel-filtered FS40 sunlamps (∼ 60% UVB and 40% UVA). Carcinoma incidence in mice treated with vehicle, 100, 200 or 500 nmol PL, at 44 weeks post-UVR, were 86, 80 (P = 0.67), 53 (P = 0.12) and 7% (P = 0.0075), respectively. Both vehicle and PL-treated mice gained weight and did not exhibit any signs of toxicity during the entire period of the experiment. Molecular mechanisms associated with inhibition of UVR-induced development of SCC involved induction of apoptosis and inhibition of cell proliferation. Specific findings are that PL treatment (i) inhibited UVR-induced DNA binding of activating protein-1, nuclear factor-kappaB, Stat3 transcription factors and Stat3-regulated molecules (cdc25A and Survivin); (ii) inhibited protein levels of pERK1/2, PI3K85, pAKTSer473, Bcl(2), BclxL, proliferating cell nuclear antigen and cell cycle inhibitory proteins p27 and p21 and (iii) increased UVR-induced Fas-associated death domain expression, poly (ADP-ribose) polymerase protein cleavage and Bax/Bcl(2) ratio. Taken together, our findings suggest that PL may be a novel agent for the prevention of skin cancer.
authors.affiliation: Molecular and Environmental Toxicology, School of Medicine and Public Health, Wisconsin Institutes of Medical Research, 1111 Highland Avenue, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Sand
authors.forename: Bilal
authors.initials: B
authors.lastname: Bin Hafeez
authors.forename: Mohammad Sarwar
authors.initials: MS
authors.lastname: Jamal
authors.forename: Olya
authors.initials: O
authors.lastname: Witkowsky
authors.forename: Emily M
authors.initials: EM
authors.lastname: Siebers
authors.forename: Joseph
authors.initials: J
authors.lastname: Fischer
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Verma
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005260:Female; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000627:therapeutic use*; D009381:Neoplasms, Radiation-Induced / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D009285:Naphthoquinones; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D018808:Transcription Factor AP-1; D004247:DNA; C014758:plumbagin
references.citation: Cancer Lett. 2008 Jan 18;259(1):82-98
references.pmid: 18023967
references.citation: Curr Treat Options Oncol. 2002 Jun;3(3):193-203
references.pmid: 12057065
references.citation: Mol Cancer Ther. 2006 Dec;5(12):3209-21
references.pmid: 17172425
references.citation: Curr Probl Dermatol. 2007;35:14-27
references.pmid: 17641487
references.citation: Cancer Res. 2004 Apr 1;64(7):2382-9
references.pmid: 15059889
references.citation: Oncogene. 2000 May 15;19(21):2607-11
references.pmid: 10851059
references.citation: Pharm Res. 2008 Sep;25(9):2171-80
references.pmid: 18213451
references.citation: Photochem Photobiol. 2005 Sep-Oct;81(5):1174-9
references.pmid: 15938647
references.citation: J Pharmacol Exp Ther. 2006 Aug;318(2):484-94
references.pmid: 16632641
references.citation: Cancer Res. 2007 Feb 1;67(3):1385-94
references.pmid: 17283176
references.citation: J Cell Biochem. 2008 Dec 15;105(6):1461-71
references.pmid: 18980240
references.citation: Mol Carcinog. 2004 Aug;40(4):201-11
references.pmid: 15264212
references.citation: J Biol Chem. 2009 Sep 4;284(36):24453-64
references.pmid: 19570987
references.citation: Mol Cell Biochem. 1993 Aug 11;125(1):59-63
references.pmid: 8264573
references.citation: J Biol Chem. 2006 Jun 23;281(25):17023-17033
references.pmid: 16624823
references.citation: Biochem Biophys Res Commun. 2004 Sep 24;322(3):1005-11
references.pmid: 15336564
references.citation: Skin Pharmacol Appl Skin Physiol. 2002 Sep-Oct;15(5):316-20
references.pmid: 12239425
references.citation: Cancer Res. 2004 Sep 1;64(17):6349-56
references.pmid: 15342425
references.citation: Indian J Med Res. 1982 Dec;76 Suppl:99-101
references.pmid: 7185760
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Ann Oncol. 2008 Apr;19(4):696-705
references.pmid: 18187487
references.citation: Mol Cancer Res. 2010 Jan;8(1):107-18
references.pmid: 20068065
references.citation: Curr Cancer Drug Targets. 2007 Jun;7(4):325-34
references.pmid: 17979627
references.citation: J Dermatol Sci. 2008 Apr;50(1):1-14
references.pmid: 17601706
references.citation: FASEB J. 2005 Jul;19(9):1193-5
references.pmid: 15837718
references.citation: J Neurochem. 2010 Mar;112(5):1316-26
references.pmid: 20028456
references.citation: Cancer Res. 2007 Sep 15;67(18):8828-38
references.pmid: 17875724
references.citation: Med Res Rev. 2012 Nov;32(6):1131-58
references.pmid: 23059762
references.citation: J Photochem Photobiol B. 2001 Oct;63(1-3):8-18
references.pmid: 11684447
references.citation: Cancer Res. 2004 Nov 1;64(21):7756-65
references.pmid: 15520180
references.citation: Cancer Lett. 1998 May 15;127(1-2):177-83
references.pmid: 9619875
references.citation: Toxicol Appl Pharmacol. 2007 Sep 15;223(3):267-76
references.pmid: 17618663
references.citation: Cancer Res. 2008 Nov 1;68(21):9024-32
references.pmid: 18974148