Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts

Heather E. Kleiner-Hancock, Runhua Shi, Angela Remeika, Delira Robbins, Misty Prince, Jennifer N. Gill, Zanobia Syed, Patrick Adegboyega, James Michael Mathis, John L. Clifford

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Abstract

Background: NF-κB 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-κB activation in NF-κB-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-κB 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.

Original languageEnglish
Article number394
JournalBMC Cancer
Volume10
DOIs
StatePublished - 26 Jul 2010

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Ginger
Citrus
Tretinoin
Heterografts
Squamous Cell Carcinoma
Acetates
Tumor Burden
Lipopolysaccharides
Neoplasms
Alpinia
SCID Mice
aurapten
Tetradecanoylphorbol Acetate
Luciferases
Transcription Factors
Diet
Phenotype
Skin
Injections
Survival

Cite this

Kleiner-Hancock, H. E., Shi, R., Remeika, A., Robbins, D., Prince, M., Gill, J. N., ... Clifford, J. L. (2010). Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts. BMC Cancer, 10, [394]. https://doi.org/10.1186/1471-2407-10-394
Kleiner-Hancock, Heather E. ; Shi, Runhua ; Remeika, Angela ; Robbins, Delira ; Prince, Misty ; Gill, Jennifer N. ; Syed, Zanobia ; Adegboyega, Patrick ; Mathis, James Michael ; Clifford, John L. / Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts. In: BMC Cancer. 2010 ; Vol. 10.
@article{23ee66ead0004be98668ca45e476815e,
title = "Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts",
abstract = "Background: NF-κB 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-κB activation in NF-κB-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-κB 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.",
author = "Kleiner-Hancock, {Heather E.} and Runhua Shi and Angela Remeika and Delira Robbins and Misty Prince and Gill, {Jennifer N.} and Zanobia Syed and Patrick Adegboyega and Mathis, {James Michael} and Clifford, {John L.}",
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Kleiner-Hancock, HE, Shi, R, Remeika, A, Robbins, D, Prince, M, Gill, JN, Syed, Z, Adegboyega, P, Mathis, JM & Clifford, JL 2010, 'Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts', BMC Cancer, vol. 10, 394. https://doi.org/10.1186/1471-2407-10-394

Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts. / Kleiner-Hancock, Heather E.; Shi, Runhua; Remeika, Angela; Robbins, Delira; Prince, Misty; Gill, Jennifer N.; Syed, Zanobia; Adegboyega, Patrick; Mathis, James Michael; Clifford, John L.

In: BMC Cancer, Vol. 10, 394, 26.07.2010.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts

AU - Kleiner-Hancock, Heather E.

AU - Shi, Runhua

AU - Remeika, Angela

AU - Robbins, Delira

AU - Prince, Misty

AU - Gill, Jennifer N.

AU - Syed, Zanobia

AU - Adegboyega, Patrick

AU - Mathis, James Michael

AU - Clifford, John L.

PY - 2010/7/26

Y1 - 2010/7/26

N2 - Background: NF-κB 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-κB activation in NF-κB-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-κB 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.

AB - Background: NF-κB 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-κB activation in NF-κB-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-κB 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.

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Kleiner-Hancock HE, Shi R, Remeika A, Robbins D, Prince M, Gill JN et al. Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts. BMC Cancer. 2010 Jul 26;10. 394. https://doi.org/10.1186/1471-2407-10-394