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Published on: December 16, 2022
Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts
Heather E Kleiner-Hancock1, Runhua Shi, Angela Remeika
1Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71103, USA. hklein@lsuhsc.edu
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.
Insights
Auraptene (AUR) and 1'-acetoxychavicol acetate (ACA) suppressed NF-kappaB activation. AUR and ACA, especially combined with all-trans retinoic acid (ATRA), showed significant potential in suppressing squamous cell carcinoma (SCC) tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- NF-kappaB is a key transcription factor in cancer survival, particularly in squamous cell carcinomas (SCC).
- Auraptene (AUR), a citrus coumarin, and 1 -acetoxychavicol acetate (ACA), a ginger-derived phenylpropanoid, are known to inhibit tumor promotion.
- This study investigates their potential in SCC tumor growth suppression.
Purpose of the Study:
- To evaluate the efficacy of AUR and ACA, alone and in combination with all-trans retinoic acid (ATRA), against SCC tumor growth.
- To assess the impact of these compounds on NF-kappaB activation.
Main Methods:
- Assessed LPS-induced NF-kappaB activation in reporter mice treated with ACA and AUR.
- Evaluated dietary administration of AUR, ACA, and ATRA in a mouse xenograft model of SCC.
- Monitored tumor volume and weight over 28 days post-injection.
Main Results:
- Both AUR and ACA inhibited LPS-induced NF-kappaB activation.
- AUR (1000 ppm) and ACA (500 ppm) showed modest suppression of tumor volume.
- ACA (500 ppm) combined with ATRA (5-30 ppm) significantly inhibited tumor volume (56-98%).
- AUR (1000 ppm) combined with ATRA (10 ppm) strongly suppressed tumor volume (84%).
Conclusions:
- AUR and ACA show promise in combination with ATRA for SCC tumor suppression.
- AUR may synergize ATRA's tumor-suppressive effects, while ACA may prolong them.
- Further research is needed to explore these combinations for human SCC treatment.
