Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

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

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

Published in: BMC Cancer | Issue 1/2010

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer Statistics, 2009. CA Cancer J Clin. 2009, 59 (4): 225-49. 10.3322/caac.20006.CrossRefPubMed
2.
Alam M, Ratner D: Cutaneous squamous-cell carcinoma. N Engl J Med. 2001, 344 (13): 975-983. 10.1056/NEJM200103293441306.CrossRefPubMed
3.
Karin M: Nuclear factor-kappaB in cancer development and progression. Nature. 2006, 441 (7092): 431-436. 10.1038/nature04870.CrossRefPubMed
4.
Aggarwal BB: Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004, 6 (3): 203-208. 10.1016/j.ccr.2004.09.003.CrossRefPubMed
5.
Kondo A, Ohigashi H, Murakami A: A potent inhibitor of tumor promoter-induced Epstein-Barr virus activation, 1'-acetoxychavicol acetate from Languas galanga, a traditional Thai condiment. Bioscience Biotechnology Biochemistry. 1993, 57: 1344-1345. 10.1271/bbb.57.1344.CrossRef
6.
Murakami A, Ohura S, Nakamura Y, Koshimizu K, Ohigashi H: 1'-Acetoxychavicol acetate, a superoxide anion generation inhibitor, potently inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in ICR mouse skin. Oncology. 1996, 53 (5): 386-391. 10.1159/000227593.CrossRefPubMed
7.
Ichikawa H, Takada Y, Murakami A, Aggarwal BB: Identification of a novel blocker of I kappa B alpha kinase that enhances cellular apoptosis and inhibits cellular invasion through suppression of NF-kappa B-regulated gene products. J Immunol. 2005, 174 (11): 7383-7392.CrossRefPubMed
8.
Murakami A, Kuki W, Takahashi Y, Yonei H, Nakamura Y, Ohto Y, Ohigashi H, Koshimizu K: Auraptene, a citrus coumarin, inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in ICR mouse skin, possibly through suppression of superoxide generation in leukocytes. Jpn J Cancer Res. 1997, 88 (5): 443-452.CrossRefPubMed
9.
Jun DY, Kim JS, Park HS, Han CR, Fang Z, Woo MH, Rhee IK, Kim YH: Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade. Carcinogenesis. 2007, 28 (6): 1303-1313. 10.1093/carcin/bgm028.CrossRefPubMed
10.
Yu L, Zhang DM: [Studies on chemical constituents from fruits of Paliurus ramosissimus]. Zhongguo Zhong Yao Za Zhi. 2006, 31 (24): 2049-2052.PubMed
11.
Murakami A, Ohigashi H: Cancer-preventive anti-oxidants that attenuate free radical generation by inflammatory cells. Biol Chem. 2006, 387 (4): 387-392. 10.1515/BC.2006.052.CrossRefPubMed
12.
Kawabata K, Murakami A, Ohigashi H: Auraptene decreases the activity of matrix metalloproteinases in dextran sulfate sodium-induced ulcerative colitis in ICR mice. Biosci Biotechnol Biochem. 2006, 70 (12): 3062-3065. 10.1271/bbb.60393.CrossRefPubMed
13.
Kohno H, Suzuki R, Curini M, Epifano F, Maltese F, Gonzales SP, Tanaka T: Dietary administration with prenyloxycoumarins, auraptene and collinin, inhibits colitis-related colon carcinogenesis in mice. Int J Cancer. 2006, 118 (12): 2936-2942. 10.1002/ijc.21719.CrossRefPubMed
14.
Kuroyanagi K, Kang MS, Goto T, Hirai S, Ohyama K, Kusudo T, Yu R, Yano M, Sasaki T, Takahashi N, et al: Citrus auraptene acts as an agonist for PPARs and enhances adiponectin production and MCP-1 reduction in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2008, 366 (1): 219-225. 10.1016/j.bbrc.2007.11.119.CrossRefPubMed
15.
Takahashi Y, Inaba N, Kuwahara S, Kuki W, Yamane K, Murakami A: Rapid and convenient method for preparing aurapten-enriched product from hassaku peel oil: implications for cancer-preventive food additives. J Agric Food Chem. 2002, 50 (11): 3193-3196. 10.1021/jf011628b.CrossRefPubMed
16.
Clagett-Dame M, DeLuca HF: The role of vitamin A in mammalian reproduction and embryonic development. Annu Rev Nutr. 2002, 22: 347-381. 10.1146/annurev.nutr.22.010402.102745E.CrossRefPubMed
17.
Maden M, Hind M: Retinoic acid, a regeneration-inducing molecule. Dev Dyn. 2003, 226 (2): 237-244. 10.1002/dvdy.10222.CrossRefPubMed
18.
Love JM, Gudas LJ: Vitamin A, differentiation and cancer. Curr Opin Cell Biol. 1994, 6 (6): 825-831. 10.1016/0955-0674(94)90051-5.CrossRefPubMed
19.
Chen L-C, De Luca LM: Retinoid effects on skin cancer. Skin Cancer: Mechanisms and human relevance. Edited by: Mukhtar H. 1994, Boca Raton: CRC Press, 401-424.
20.
Verma AK: Inhibition of both stage I and stage II mouse skin tumour promotion by retinoic acid and the dependence of inhibition of tumor promotion on the duration of retinoic acid treatment. Cancer Res. 1987, 47 (19): 5097-5101.PubMed
21.
Cheepala SB, Yin W, Syed Z, Gill JN, McMillian A, Kleiner HE, Lynch M, Loganantharaj R, Trutschl M, Cvek U, et al: Identification of the B-Raf/Mek/Erk MAP kinase pathway as a target for all-trans retinoic acid during skin cancer promotion. Mol Cancer. 2009, 8: 27-10.1186/1476-4598-8-27.CrossRefPubMedPubMedCentral
22.
Syed Z, Cheepala SB, Gill JN, Stein J, Nathan CA, DiGiovanni J, Batra V, Adegboyega P, Kleiner HE, Clifford JL: All-trans retinoic acid suppresses Stat3 signaling during skin carcinogenesis. Cancer Prevention Research. 2009, 2: 903-911. 10.1158/1940-6207.CAPR-09-0041.CrossRefPubMed
23.
Carlsen H, Moskaug JO, Fromm SH, Blomhoff R: In vivo imaging of NF-kappa B activity. J Immunol. 2002, 168 (3): 1441-1446.CrossRefPubMed
24.
Barwick T, Bencherif B, Mountz JM, Avril N: Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation. Nucl Med Commun. 2009, 30 (12): 908-917. 10.1097/MNM.0b013e32832ee93b.CrossRefPubMed
25.
Martin SJ, Eisenbarth JA, Wagner-Utermann U, Mier W, Henze M, Pritzkow H, Haberkorn U, Eisenhut M: A new precursor for the radiosynthesis of [18F]FLT. Nucl Med Biol. 2002, 29 (2): 263-273. 10.1016/S0969-8051(01)00289-X.CrossRefPubMed
26.
Habig WH, Jakoby WB: Assays for differentiation of glutathione S-transferases. Methods Enzymol. 1981, 77: 398-405. full_text.CrossRefPubMed
27.
Kleiner HE, Vulimiri SV, Miller L, Johnson WH, Whitman CP, DiGiovanni J: Oral administration of naturally occurring coumarins leads to altered phase I and II enzyme activities and reduced DNA adduct formation by polycyclic aromatic hydrocarbons in various tissues of SENCAR mice. Carcinogenesis. 2001, 22 (1): 73-82. 10.1093/carcin/22.1.73.CrossRefPubMed
28.
Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254. 10.1016/0003-2697(76)90527-3.CrossRefPubMed
29.
Habig WH, Pabst MJ, Jakoby WB: Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem. 1974, 249 (22): 7130-7139.PubMed
30.
Prochaska HJ, Talalay P: Purification and characterization of two isofunctional forms of NAD(P)H: quinone reductase from mouse liver. J Biol Chem. 1986, 261 (3): 1372-1378.PubMed
31.
Kawabata K, Tanaka T, Yamamoto T, Ushida J, Hara A, Murakami A, Koshimizu K, Ohigashi H, Stoner GD, Mori H: Suppression of N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis by dietary feeding of 1'-acetoxychavicol acetate. Jpn J Cancer Res. 2000, 91 (2): 148-155.CrossRefPubMed
32.
Nakamura Y, Murakami A, Ohto Y, Torikai K, Tanaka T, Ohigashi H: Suppression of tumor promoter-induced oxidative stress and inflammatory responses in mouse skin by a superoxide generation inhibitor 1'-acetoxychavicol acetate. Cancer Res. 1998, 58 (21): 4832-4839.PubMed
33.
Tanaka T, Kawabata K, Kakumoto M, Makita H, Matsunaga K, Mori H, Satoh K, Hara A, Murakami A, Koshimizu K, et al: Chemoprevention of azoxymethane-induced rat colon carcinogenesis by a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate. Jpn J Cancer Res. 1997, 88 (9): 821-830.CrossRefPubMed
34.
Ohnishi M, Tanaka T, Makita H, Kawamori T, Mori H, Satoh K, Hara A, Murakami A, Ohigashi H, Koshimizu K: Chemopreventive effect of a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate, on rat oral carcinogenesis. Jpn J Cancer Res. 1996, 87 (4): 349-356.CrossRefPubMed
35.
Prince M, Li Y, Childers A, Itoh K, Yamamoto M, Kleiner HE: Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice. Toxicol Lett. 2009, 185 (3): 180-186. 10.1016/j.toxlet.2008.12.014.CrossRefPubMed
36.
Murakami A, Wada K, Ueda N, Sasaki K, Haga M, Kuki W, Takahashi Y, Yonei H, Koshimizu K, Ohigashi H: In vitro absorption and metabolism of a citrus chemopreventive agent, auraptene, and its modifying effects on xenobiotic enzyme activities in mouse livers. Nutr Cancer. 2000, 36 (2): 191-199. 10.1207/S15327914NC3602_8.CrossRefPubMed
37.
Hayes JD, Pulford DJ: The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995, 30 (6): 445-600. 10.3109/10409239509083491.CrossRefPubMed
38.
Surh YJ: Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 2003, 3 (10): 768-780. 10.1038/nrc1189.CrossRefPubMed
39.
Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR: Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev. 2007, 21 (11): 1396-1408. 10.1101/gad.1553707.CrossRefPubMedPubMedCentral
40.
Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll DM, Yu H: Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell. 2009, 15 (4): 283-293. 10.1016/j.ccr.2009.02.015.CrossRefPubMedPubMedCentral
41.
Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, et al: Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res. 2009, 15 (10): 3423-3432. 10.1158/1078-0432.CCR-08-2822.CrossRefPubMed
42.
Wang XJ, Hayes JD, Henderson CJ, Wolf CR: Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci USA. 2007, 104 (49): 19589-19594. 10.1073/pnas.0709483104.CrossRefPubMedPubMedCentral
43.
Hu L, Miao W, Loignon M, Kandouz M, Batist G: Putative chemopreventive molecules can increase Nrf2-regulated cell defense in some human cancer cell lines, resulting in resistance to common cytotoxic therapies. Cancer Chemother Pharmacol. 2010, 66 (3): 467-74. 10.1007/s00280-009-1182-7.CrossRefPubMed
44.
Tan KP, Kosuge K, Yang M, Ito S: NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicity. Free Radic Biol Med. 2008, 45 (12): 1663-1673. 10.1016/j.freeradbiomed.2008.09.010.CrossRefPubMed
Metadata
Title
Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts
Authors
Heather E Kleiner-Hancock
Runhua Shi
Angela Remeika
Delira Robbins
Misty Prince
Jennifer N Gill
Zanobia Syed
Patrick Adegboyega
J Michael Mathis
John L Clifford
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-394

Other articles of this Issue 1/2010

BMC Cancer 1/2010 Go to the issue

Research article

Mechanism of endothelial progenitor cell recruitment into neo-vessels in adjacent non-tumor tissues in hepatocellular carcinoma

Research article

Overexpression of sphingosine kinase 1 is associated with salivary gland carcinoma progression and might be a novel predictive marker for adjuvant therapy

Research article

Differential expression of anterior gradient gene AGR2 in prostate cancer

Research article

Degradation of HER2/neu by ANT2 shRNA suppresses migration and invasiveness of breast cancer cells

Research article

Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response

Research article

MAL2 and tumor protein D52 (TPD52) are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits