Abstract 1881: Plumbagin, a medicinal plant-derived naphthoquinone, inhibits ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC 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 Plumbago zeylanica have been used in Indian medicine for more than 2,500 years for treatments of various ailments. PL is also present in black walnut and other various medicinal plants. In Ayurveda, this herb is considered one of the most potent medicines used for various skin ailments, like leucoderma, psoriasis, leprosy, and scabies. We present here that topical application of non-toxic doses (100-500 nmoles) of PL to skin elicits dose-dependent inhibition of ultraviolet radiation (UVR)-induced cutaneous damage and development of squamous cell carcinomas (SCC). In this experiment, FVB/N mice were exposed to UVR (2 kJ/m2) three times weekly from a bank of six kodacel-filtered FS40 sunlamps (approximately 60% UVB and 40% UVA). The vehicle acetone or the indicated doses of PL in 0.2 ml acetone were applied to the dorsal skin 15 min after UVR exposure. Carcinoma incidence in mice treated with vehicle, 100, 200 or 500 nmoles PL, at 44 weeks post UVR, were 86%, 80% (p=0.67), 53% (p=0.06) and 7% (p=0.0025), respectively. Both vehicle and PL treated mice gained weight and did not exhibit any sign of toxicity during the entire period of the experiment. The molecular mechanisms associated with inhibition of UVR-induced development of SCC involved both induction of apoptosis and inhibition of cell proliferation. Specific findings are that PL treatment increased UVR-induced expression of fas-associated death domain (FADD) protein, Bax, p21, p27 and PARP cleavage. PL treatment also inhibited cell survival by decreasing the expression of pERK1/2, p85 PI3K, pAKT(ser473), Bcl2, and BclXL. Plumbagin also inhibited constitutive activation of transcription factors Stat3, NF-kB and AP-1. In summary, PL has been shown to exert both anticancer and antiproliferative activities in animal models as well as in cell culture. For example, PL, fed in the diet (200 ppm), significantly inhibits azoxymethane-induced intestinal tumors in rat. PL has chemotherapeutic potential as an anti-cancer agent. PL inhibits ectopic growth of breast cancer cells MDA-MB-231, nonsmall cell lung cancer cells A549, melanoma A375-52 cells and prostate cancer DU145 cells in nude mice (J Biol Chem 2006,281:17023, Cancer Res. 2008, 68:9024). We have now shown that PL inhibits the induction of SCC elicited by UVR, the most ubiquitous environmental carcinogen. Taken together, we conclude that PL may be explored as a naturally occurring agent in the prevention and treatment of human cancers (Support: NIH grants CA102431, CA35368 and T32ES007015) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1881.