Kleiner-Hancock et al. BMC Cancer 2010, 10:394 http://www.biomedcentral.com/1471-2407/10/394 R E S E A R C H A R T I C L E Open Access Effects of ATRA combined with citrus and ginger- derived compounds in human SCC xenografts Heather E Kleiner-Hancock1,6*, Runhua Shi2,6, Angela Remeika1, Delira Robbins1, Misty Prince1, Jennifer N Gill3, Zanobia Syed3, Patrick Adegboyega4,6, J Michael Mathis5,6, John L Clifford3,6 Abstract Background: NF- B is a survival signaling transcription factor complex involved in the malignant phenotype of many cancers, including squamous cell carcinomas (SCC). The citrus coumarin, auraptene (AUR), and the ethno- medicinal ginger (Alpinia galanga) phenylpropanoid, 1’-acetoxychavicol acetate (ACA), were previously shown to suppress 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse skin tumor promotion. The goal of the present study was to determine whether AUR and ACA are effective either alone or in combination with all-trans retinoic acid (ATRA) for suppressing SCC tumor growth. Methods: We first determined the effects of orally administered ACA (100 mg/kg bw) and AUR (200 mg/kg bw) on lipopolysaccharide (LPS)-induced NF- B activation in NF- B-RE-luc (Oslo) luciferase reporter mice. Dietary administration of AUR and ACA ± ATRA was next evaluated in a xenograft mouse model. Female SCID/bg mice were fed diets containing the experimental compounds, injected with 1 × 106 SRB12-p9 cells s.c., palpated and weighed twice a week for 28 days following injection. Results: Both ACA and AUR suppressed LPS-induced NF- B activation in the report mice. In the xenograft model, AUR (1000 ppm) and ACA (500 ppm) modestly suppressed tumor volume. However, in combination with ATRA at 5, 10, and 30 ppm, ACA 500 ppm significantly inhibited tumor volume by 56%, 62%, and 98%, respectively. The effect of ATRA alone was 37%, 33%, and 93% inhibition, respectively. AUR 1000 ppm and ATRA 10 ppm were not very effective when administered alone, but when combined, strongly suppressed tumor volume by 84%. Conclusions: Citrus AUR may synergize the tumor suppressive effects of ATRA, while ACA may prolong the inhibitory effects of ATRA. Further studies will be necessary to determine whether these combinations may be useful in the control of human SCC. Background Non-melanoma skin cancer (NMSC) is the most com- mon cancer in the U.S., with over a million new cases of the two most common forms, squamous cell carci- noma (SCC) and basal cell carcinoma (BCC), anticipated annually [1]. The more clinically aggressive form is SCC of the skin [2], which has been increasing in incidence since the 1960 s at annual rates from 4% to as much as 10% in recent years. Better control of advanced skin SCC is clearly necessary, and will be helped by improv- ing our understanding of the molecular basis for skin * Correspondence: hklein@lsuhsc.edu 1Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Hwy, Shreveport, Louisiana, 71103 USA carcinogenesis and of the action of chemopreventive drugs. Nuclear factor B (NF- B) is activated during inflam- mation and carcinogenesis [3]. Lipopolysaccharide (LPS), interleukin-1b, hydrogen peroxide, and tumor necrosis factor activate NF- B signaling through phos- phorylation of its inhibitor I Ba. This leads to degrada- tion of I Ba, phosphorylation of the p65 NF- B subunit, and translocation of p65, along with the p50 subunit, to the nucleus. There they form a DNA binding complex and activate transcription of specific genes involved in proliferation (cyclin D1, c-myc, COX-2), angiogenesis (vascular endothelial growth factor-VEGF), antiapoptosis (survivin, TRAF1, IAP1, BclXL, FLIP) and invasion (matrix metalloproteinase 9, ICAM-1) [4]. © 2010 Kleiner-Hancock et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.