Effects of combined phytochemicals on skin tumorigenesis in SENCAR mice

Kowalczyk,Magdalena C.; Junco,Jacob J.; Kowalczyk,Piotr; Tolstykh,Olga; Hanausek,Margaret; Slaga,Thomas  J.; Walaszek,Zbigniew

doi:10.3892/ijo.2013.2005

Effects of combined phytochemicals on skin tumorigenesis in SENCAR mice

Authors:
- Magdalena C. Kowalczyk
- Jacob J. Junco
- Piotr Kowalczyk
- Olga Tolstykh
- Margaret Hanausek
- Thomas J. Slaga
- Zbigniew Walaszek
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Affiliations: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Published online on: July 5, 2013 https://doi.org/10.3892/ijo.2013.2005
Pages: 911-918

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Abstract

The purpose of our study was to determine the effect of the combined action of phytochemicals on the early stages of skin tumorigenesis, i.e. initiation and promotion. We tested calcium D-glucarate (CG) given in the diet, while resveratrol (RES) and ursolic acid (UA) were applied topically. The 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted multistage skin carcinogenesis model in SENCAR mice was used. Mice received one topical dose of DMBA, then after one month, two weekly doses of TPA for 14 weeks until sacrifice. RES or UA were applied 20 min prior to DMBA or TPA treatment and 2% dietary CG was given from 2 weeks prior to 2 weeks after the DMBA dose or continually beginning 2 weeks prior to the first dose of TPA. UA applied alone and in combination with CG during the promotion stage was the only inhibitor of tumor multiplicity and tumor incidence. A number of combinations reduced epidermal proliferation, but only UA and the combination UA+CG applied during promotion significantly reduced epidermal hyperplasia. DMBA/TPA application resulted in significant increases in c-jun and p50, which were reversed by a number of different treatments. DMBA/TPA treatment also strongly increased mRNA levels of inflammation markers COX-2 and IL-6. All anti-promotion treatments caused a marked decrease in COX-2 and IL-6 expression compared to the DMBA/TPA control. These results show that UA is a potent inhibitor of skin tumor promotion and inflammatory signaling and it may be useful in the prevention of skin cancer and other epithelial cancers in humans.

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1	Bishop JM: Molecular themes in oncogenesis. Cell. 64:235–248. 1991. View Article : Google Scholar : PubMed/NCBI
2	Knudson AG: Hereditary predisposition to cancer. Ann NY Acad Sci. 833:58–67. 1997. View Article : Google Scholar : PubMed/NCBI
3	Boutwell RK: Some biological aspects of skin carcinogenisis. Prog Exp Tumor Res. 4:207–250. 1964.PubMed/NCBI
4	Slaga TJ: Cancer: etiology, mechanisms, and prevention - a summary. Carcinog Compr Surv. 5:243–262. 1980.PubMed/NCBI
5	DiGiovanni J: Multistage carcinogenesis in mouse skin. Pharmacol Ther. 54:63–128. 1992. View Article : Google Scholar : PubMed/NCBI
6	Kemp CJ: Multistep skin cancer in mice as a model to study the evolution of cancer cells. Semin Cancer Biol. 15:460–473. 2005. View Article : Google Scholar : PubMed/NCBI
7	Perez-Losada J and Balmain A: Stem-cell hierarchy in skin cancer. Nat Rev Cancer. 3:434–443. 2003. View Article : Google Scholar : PubMed/NCBI
8	Hanausek M, Ganesh P, Walaszek Z, Arntzen CJ, Slaga TJ and Gutterman JU: Avicins, a family of triterpenoid saponins from Acacia victoriae(Bentham), suppress H-ras mutations and aneuploidy in a murine skin carcinogenesis model. Proc Natl Acad Sci USA. 98:11551–11556. 2001.PubMed/NCBI
9	Kim EJ, Park H, Kim J and Park JH: 3,3′-diindolylmethane suppresses 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin via the downregulation of inflammatory mediators. Mol Carcinog. 49:672–683. 2010.
10	Budunova IV, Perez P, Vaden VR, Spiegelman VS, Slaga TJ and Jorcano JL: Increased expression of p50-NF-kappaB and constitutive activation of NF-kappaB transcription factors during mouse skin carcinogenesis. Oncogene. 18:7423–7431. 1999. View Article : Google Scholar : PubMed/NCBI
11	Przybyszewski J, Yaktine AL, Duysen E, et al: Inhibition of phorbol ester-induced AP-1-DNA binding, c-Jun protein and c-jun mRNA by dietary energy restriction is reversed by adrenalectomy in SENCAR mouse epidermis. Carcinogenesis. 22:1421–1427. 2001. View Article : Google Scholar : PubMed/NCBI
12	Walaszek Z, Hanausek M and Slaga TJ: Mechanisms of chemoprevention. Chest. 125:S128–S133. 2004. View Article : Google Scholar
13	Taesotikul T, Dumrongsakulchai W, Wattanachai N, Navinpipat V, Somanabandhu A and Tassaneeyakul W: Inhibitory effects of Phyllanthus amarus and its major lignans on human microsomal cytochrome P450 activities: evidence for CYP3A4 mechanism-based inhibition. Drug Metab Pharmacokinet. 26:154–161. 2011. View Article : Google Scholar
14	Kimura Y, Ito H, Ohnishi R and Hatano T: Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity. Food Chem Toxicol. 48:429–435. 2010. View Article : Google Scholar : PubMed/NCBI
15	Suganuma M, Okabe S, Kai Y, Sueoka N, Sueoka E and Fujiki H: Synergistic effects of (−)-epigallocatechin gallate with (−)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9. Cancer Res. 59:44–47. 1999.
16	Saw CL, Cintron M, Wu TY, et al: Pharmacodynamics of dietary phytochemical indoles I3C and DIM: induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates. Biopharm Drug Dispos. 32:289–300. 2011. View Article : Google Scholar : PubMed/NCBI
17	Khafif A, Schantz SP, Chou TC, Edelstein D and Sacks PG: Quantitation of chemopreventive synergism between (−)-epigallocatechin-3-gallate and curcumin in normal, premalignant and malignant human oral epithelial cells. Carcinogenesis. 19:419–424. 1998.
18	Vingtdeux V, Dreses-Werringloer U, Zhao H, Davies P and Marambaud P: Therapeutic potential of resveratrol in Alzheimer’s disease. BMC Neurosci. 9(Suppl 2): S62008.
19	Bishayee A: Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res. 2:409–418. 2009. View Article : Google Scholar : PubMed/NCBI
20	Das M and Das DK: Resveratrol and cardiovascular health. Mol Aspects Med. 31:503–512. 2010. View Article : Google Scholar : PubMed/NCBI
21	Brasnyo P, Molnar GA, Mohas M, et al: Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 106:383–389. 2011. View Article : Google Scholar : PubMed/NCBI
22	Howells LM, Berry DP, Elliott PJ, et al: Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res. 4:1419–1425. 2011. View Article : Google Scholar : PubMed/NCBI
23	Patel KR, Brown VA, Jones DJ, et al: Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 70:7392–7399. 2010. View Article : Google Scholar : PubMed/NCBI
24	Walaszek Z, Szemraj J, Narog M, et al: Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer prevention. Cancer Detect Prev. 21:178–190. 1997.PubMed/NCBI
25	Yoshimi N, Walaszek Z, Mori H, Hanausek M, Szemraj J and Slaga TJ: Inhibition of azoxymethane-induced rat colon carcinogenesis by potassium hydrogen D-glucarate. Int J Oncol. 16:43–48. 2000.PubMed/NCBI
26	Hanausek M, Walaszek Z and Slaga TJ: Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2:139–144. 2003. View Article : Google Scholar : PubMed/NCBI
27	Abou-Issa H, Moeschberger M, el-Masry W, Tejwani S, Curley RW Jr and Webb TE: Relative efficacy of glucarate on the initiation and promotion phases of rat mammary carcinogenesis. Anticancer Res. 15:805–810. 1995.PubMed/NCBI
28	Huang MT, Ho CT, Wang ZY, et al: Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res. 54:701–708. 1994.PubMed/NCBI
29	De Angel RE, Smith SM, Glickman RD, Perkins SN and Hursting SD: Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer. Nutr Cancer. 62:1074–1086. 2010.PubMed/NCBI
30	Shan JZ, Xuan YY, Zheng S, Dong Q and Zhang SZ: Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. J Zhejiang Univ Sci B. 10:668–674. 2009. View Article : Google Scholar : PubMed/NCBI
31	Kassi E, Papoutsi Z, Pratsinis H, Aligiannis N, Manoussakis M and Moutsatsou P: Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. J Cancer Res Clin Oncol. 133:493–500. 2007. View Article : Google Scholar
32	Kassi E, Sourlingas TG, Spiliotaki M, et al: Ursolic acid triggers apoptosis and Bcl-2 downregulation in MCF-7 breast cancer cells. Cancer Invest. 27:723–733. 2009. View Article : Google Scholar : PubMed/NCBI
33	Fischer SM, Pavone A, Mikulec C, Langenbach R and Rundhaug JE: Cyclooxygenase-2 expression is critical for chronic UV-induced murine skin carcinogenesis. Mol Carcinog. 46:363–371. 2007. View Article : Google Scholar : PubMed/NCBI
34	Lederle W, Depner S, Schnur S, et al: IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines. Int J Cancer. 128:2803–2814. 2011. View Article : Google Scholar : PubMed/NCBI
35	Ullevig SL, Zhao Q, Zamora D and Asmis R: Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis. Atherosclerosis. 219:409–416. 2011. View Article : Google Scholar : PubMed/NCBI
36	Young MR, Li JJ, Rincon M, et al: Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA. 96:9827–9832. 1999. View Article : Google Scholar : PubMed/NCBI
37	Thompson EJ, MacGowan J, Young MR, Colburn N and Bowden GT: A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion. Cancer Res. 62:3044–3047. 2002.PubMed/NCBI
38	Kowalczyk MC, Walaszek Z, Kowalczyk P, Kinjo T, Hanausek M and Slaga TJ: Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: implications for skin cancer prevention. Carcinogenesis. 30:1008–1015. 2009. View Article : Google Scholar : PubMed/NCBI
39	Shahin V, Ludwig Y, Schafer C, Nikova D and Oberleithner H: Glucocorticoids remodel nuclear envelope structure and permeability. J Cell Sci. 118:2881–2889. 2005. View Article : Google Scholar : PubMed/NCBI
40	Thompson S and Slaga TJ: The effects of dexamethasone on mouse skin initiation and aryl hydrocarbon hydroxylase. Eur J Cancer. 12:363–370. 1976. View Article : Google Scholar : PubMed/NCBI
41	Baynes RE, Halling KB and Riviere JE: The influence of diethyl-m-toluamide (DEET) on the percutaneous absorption of permethrin and carbaryl. Toxicol Appl Pharmacol. 144:332–339. 1997. View Article : Google Scholar : PubMed/NCBI
42	Baynes RE, Brownie C, Freeman H and Riviere JE: In vitro percutaneous absorption of benzidine in complex mechanistically defined chemical mixtures. Toxicol Appl Pharmacol. 141:497–506. 1996. View Article : Google Scholar : PubMed/NCBI
43	Williams AC and Barry BW: Penetration enhancers. Adv Drug Deliv Rev. 56:603–618. 2004. View Article : Google Scholar
44	Banerjee S, Bueso-Ramos C and Aggarwal BB: Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 62:4945–4954. 2002.PubMed/NCBI
45	Cui X, Jin Y, Hofseth AB, et al: Resveratrol suppresses colitis and colon cancer associated with colitis. Cancer Prev Res. 3:549–559. 2010. View Article : Google Scholar : PubMed/NCBI
46	Harper CE, Patel BB, Wang J, Arabshahi A, Eltoum IA and Lamartiniere CA: Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis. 28:1946–1953. 2007. View Article : Google Scholar : PubMed/NCBI
47	George J, Singh M, Srivastava AK, et al: Resveratrol and black tea polyphenol combination synergistically suppress mouse skin tumors growth by inhibition of activated MAPKs and p53. PLoS One. 6:e233952011. View Article : Google Scholar : PubMed/NCBI
48	Kapadia GJ, Azuine MA, Tokuda H, et al: Chemopreventive effect of resveratrol, sesamol, sesame oil and sunflower oil in the Epstein-Barr virus early antigen activation assay and the mouse skin two-stage carcinogenesis. Pharmacol Res. 45:499–505. 2002. View Article : Google Scholar
49	Kowalczyk MC, Kowalczyk P, Tolstykh O, Hanausek M, Walaszek Z and Slaga TJ: Synergistic effects of combined phytochemicals and skin cancer prevention in SENCAR mice. Cancer Prev Res. 3:170–178. 2010. View Article : Google Scholar : PubMed/NCBI