Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts.
BACKGROUND
NF-kappaB 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-kappaB activation in NF-kappaB-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 x 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-kappaB 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.
Kleiner-Hancock
Heather E
HE
Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71103, USA. hklein@lsuhsc.edu
Shi
Runhua
R
Remeika
Angela
A
Robbins
Delira
D
Prince
Misty
M
Gill
Jennifer N
JN
Syed
Zanobia
Z
Adegboyega
Patrick
P
Mathis
J Michael
JM
Clifford
John L
JL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001592:Benzyl Alcohols / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002957:Citrus / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D020939:Zingiber officinale / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001592:Benzyl Alcohols; D003374:Coumarins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010936:Plant Extracts; D014212:Tretinoin; D008156:Luciferases; C105832:aurapten; C047948:1'-acetoxychavicol acetate