Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), isolated from Plumbago zeylanica, inhibits ultraviolet radiation-induced development of squamous cell carcinomas

Jordan M. Sand, Bilal Hafeez, Mohammad Sarwar Jamal, Olya Witkowsky, Emily M. Siebers, Joseph Fischer, Ajit K. Verma

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)184-190
Number of pages7
JournalCarcinogenesis
Volume33
Issue number1
DOIs
StatePublished - Jan 9 2012
Externally publishedYes

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Plumbaginaceae
Squamous Cell Carcinoma
Radiation
NFI Transcription Factors
Cardiotonic Agents
Naphthoquinones
bcl-2-Associated X Protein
Cell Cycle Proteins
Poly(ADP-ribose) Polymerases
Proliferating Cell Nuclear Antigen
DNA-Binding Proteins
Neuroprotective Agents
Skin Neoplasms
Medicinal Plants
plumbagin
Transcription Factors
Cell Proliferation
Medicine
Apoptosis
Carcinoma

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), isolated from Plumbago zeylanica, inhibits ultraviolet radiation-induced development of squamous cell carcinomas. / Sand, Jordan M.; Hafeez, Bilal; Jamal, Mohammad Sarwar; Witkowsky, Olya; Siebers, Emily M.; Fischer, Joseph; Verma, Ajit K.

In: Carcinogenesis, Vol. 33, No. 1, 09.01.2012, p. 184-190.

Research output: Contribution to journalArticle

Sand, Jordan M. ; Hafeez, Bilal ; Jamal, Mohammad Sarwar ; Witkowsky, Olya ; Siebers, Emily M. ; Fischer, Joseph ; Verma, Ajit K. / Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), isolated from Plumbago zeylanica, inhibits ultraviolet radiation-induced development of squamous cell carcinomas. In: Carcinogenesis. 2012 ; Vol. 33, No. 1. pp. 184-190.
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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.",
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AU - Hafeez, Bilal

AU - Jamal, Mohammad Sarwar

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AU - Siebers, Emily M.

AU - Fischer, Joseph

AU - Verma, Ajit K.

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