Abstract
There are over 1 million cases of skin cancer diagnosed yearly in the United States. The majority of these are nonmelanoma (NMSCs) and are associated with chronic exposure to ultraviolet light (UV). Actinic keratosis (AK) has been identified as a precursor for SCC, but not for BCC. AKs are far more common than SCC, making them excellent targets for chemoprevention. Cancer chemoprevention can prevent or delay the occurrence of cancer in highrisk populations using dietary or chemical interventions. We have developed strategies that have rational mechanisms of action and demonstrate activity in preclinical models of skin cancer. Promising agents proceed to phase I–III trials in subjects at high risk of skin cancer. UV light induces molecular signaling pathways and results in specific genetic alterations (i.e., mutation of p53) that are likely critical to skin cancer development. UVB-induced changes serve as a basis for the development of novel agents. Targets include inhibition of polyamine or prostaglandin synthesis, specific retinoid receptors, and components of the Ras and MAP kinase signaling pathways. Agents under study include: epigallocatechin gallate (EGCG), a green tea catechin with antioxidant and sunscreen activity, as well as UVB signal transduction blocking activity; perillyl alcohol, a monoterpene derived from citrus peel that inhibits Ras farnesylation; difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase and polyamines; retinoids that target retinoid X receptors and AP-l activity; and nonsteroidal anti-intlammatory agents that inhibit cyclooxygenase and prostaglandin synthesis. We performed a series of Phase I–II trials in subjects with multiple AK. For example, a phase II randomized trial of topical DFMO reduced AK number, suppressed polyamines, and reduced p53 protein. Our goal is to develop agents for use in combination and/or incorporation into sunscreens to improve chemoprevention efficacy and reduce skin cancer incidence.
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Ahmad N, Mukhtar H (1999) Green tea polyphenols and cancer: biologic mechanisms and practical implications. Nutr Rev 57:78–83
Alberts DS, Dorr RT, Einspahr JG, Aickin M, Saboda K, Xu MJ, Peng YM, Goldman R, Foote JA, Warneke JA, Salasche S, Roe DJ, Bowden GT (2000) Chemoprevention of human actinic kerotoses by topical 2-(difluoromethyl)-dl-ornithine. Cancer Epidemiol Biomarkers Prev 9:1281–1286
Bardon S, Picard K, Martel P (1998) Monoterpenes inhibit cell growth, cell cyele progression, and cyclin Dl gene expression in human breast cancer cell lines. Nutr Cancer 32:1–7
Barthelman M, Bair WB3rd, Stickland KK, Chen W, Timmermann BN, Valcic S, Dong Z, Bowden GT (1998) (−)-Epigallocatechin-3-gallate inhibition of ultraviolet B-induced AP-1 activity. Carcinogenesis 19:2201–2204
Barthelman M, Chen W, Gensler HL, Huang C, Dong Z, Bowden GT (1998) Inhibitory effects of perillyl alcohol on UVB-induced murine skin cancer and AP-1 transactivation. Cancer Res 58:711–716
Boone CW, Kelloff GJ, Malone WE (1990) Identification of candidate cancer chemopreventive agents and their evaluation in animal models and human clinical trials: a review. Cancer Res 50:2–9
Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Ponten J (1991) A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 88:10124–10128
Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ (1996) Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Investig Dermatol Symp Proc 1:136–42
Campbell C, Quinn AG, Angus B, Farr PM, Rees JL (1993) Wavelength specific patterns of p53 induction in human skin following exposure to UV radiation. Cancer Res 53:2697–2699
Chen W, Dong Z, Valcic S, Timmermann BN, Bowden GT (1999) Inhibition of ultraviolet Binduced c-fos gene expression and p38 mitogen-activated protein kinase activation by (−)-epigallocatechin gallate in a human kerat inocyte cell line. Mol Carcinog 24:79–84
Chen W, Tang Q, Gonzales MS, Bowden GT (2001) Role of p38 MAP kinases and ERK in mediating ultraviolet-B induced cyclooxygenase-2 gene expression in human keratinocytes. Oncogene 20:3921–3926
Chen YR, Wang W, Kong AN, Tan TH (1998) Molecular mechanisms of c-Iun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates. J Biol Chem 273:1769–1775
Chung JY, Huang C, Meng X, Dong Z, Yang CS (1999) Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved. Cancer Res 59:4610–4617
Cockerell CJ (2000) Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol 42:11–17
Crowell PL (1999) Prevention and therapy of cancer by dietary monoterpenes. J Nutr 129:775S–778S
Crowell PL, Ren Z, Lin S, Vedejs E, Gould MN (1994) Structure-activity relationships among monoterpene inhibitors of protein isoprenylation and cell proliferation. Biochem Pharmacol 47: 1405–1415
DiSepio D, Sutter M, Johnson AT, Chandraratna RA, Nagpal S (1999) Identification of the AP1-antagonism domain of retinoic acid receptors. Mol Cell Biol Res Commun 1:7–13
Dodson JM, DeSpain J, Hewett JE, Clark DP (1991) Malignant potential of actinic keratoses and the controversy over treatment. A patient-oriented perspective. Arch Dermatol 127:1029–1031
Dong Z, Birrer MJ, Watts RG, Matrisian LM, Colburn NH (1994) Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc Natl Acad Sci USA 91:609–613
Dong Z, Huang C, Ma WY (1999) PI-3 kinase in signal transduction, cell transformation, and as a target for chemoprevention of cancer. Anticancer Res 19:3743–3748
Einspahr JG, Nelson MA, Saboda K, Warneke J, Bowden GT, Alberts DS (2002) Modulation of biologic endpoints by topical difluoromethylornithine (DFMO), in subjects at high-risk for nonmelanoma skin cancer. Clin Cancer Res 8:149–155
Evans TR, Kaye SB (1999) Retinoids: present role and future potential. Br J Cancer 80:1–8
Fanjul A, Dawson MI, Hobbs PD, Long L, Cameron JF, Harlev E, Graupner G, Lu XP, Pfahl M (1994) A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 372:107–111
Fischer SM, Lee M, Lubet RA (2001) Difluoromethylornithine is effective as both a preventive and therapeutic agent against the development of UV carcinogenesis in SKH hairless mice. Carcinogenesis 22:83–88
Fischer SM, Lo HH, Gordon GB, Seibert K, Kelloff G, Lubet RA, Conti CJ (1999) Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol Carcinog 25:231–240
Fisher GJ, Talwar HS, Lin J, Lin P, McPhillips F, Wang Z, Li X, Wan Y, Kang S, Voorhees II (1998) Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest 101:1432–1440
Frankel DH, Hanusa BH, Zitelli JA (1992) New primary nonmelanoma skin cancer in patients with a history of squamous cell carcinoma of the skin. Implications and recommendations for follow-up. J Am Acad Dermatol 26:720–726
Fritzgerald DA (1998) Cancer precursors. Semin Cut Med Surg 17:108–113
Gensler HL (1991) Prevention by alpha-difluoromethylornithine of skin carcinogenesis and immunosuppression induced by ultraviolet irradiation. J Cancer Res Clin Oncol 117:345–350
Gilchrest BA, Eller MS, Geller AC, Yaar M (1999) The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 340:1341–1348
Gilmour SK, Verma AK, Madara T, O’Brien TG (1987) Regulation of ornithine decarboxylase gene expression in mouse epidermis and epidermal tumors during two-stage tumorigenesis. Cancer Res 47:1221–1225
Greenlee RT, Murray T, Bolden S, Wingo PA (2000) Cancer statistics, 2000. CA Cancer J Clin 50:7–33
Gujuluva CN, Baek JH, Shin KH, Cherrick HM, Park NH (1994) Effect of UV-irradiation on cell cycle, viability and the expression of p53, gadd153 and gadd45 genes in normal and HPV-immortalized human oral keratinocytes. Oncogene 9:1819–1827
Hall PA, McKee PH, Menage HD, Dover R, Lane DP (1993) High levels of p53 protein in UV-irradiated normal human skin. Oncogene 8:203–207
Halpern AC, Schuchter LM, Elder DE, Guerry DT, Elenitsas R, Trock B, Matozzo I (1994) Effects of topical tretinoin on dysplastic nevi. J Clin Oncol 12:1028–1035
Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M (1996) Nonmelanoma skin cancer and solar keratoses II analytical results of the South Wales Skin Cancer Study. Br J Cancer 74:1308–1312
Healy E, Reynolds NJ, Smith MD, Campbell C, Farr PM, Rees JL (1994) Dissociation of erythema and p53 protein expression in human skin following UVB irradiation, and induction of p53 protein and mRNA following application of skin irritants. J Invest Dermatol 103:493–499
Huang C, Li J, Chen N, Ma W, Bowden GT, Dong Z (2000) Inhibition of atypical PKC blocks ultraviolet-induced AP-1 activation by specifically inhibiting ERKs activation. Mol Carcinog 27:65–75
Huang C, Ma W, Bowden GT, Dong Z (1996) Ultraviolet B-induced activated protein-1 activation does not require epidermal growth factor receptor but is blocked by a dominant negative PKClambda/iota. J Biol Chem 271:31262–31268
Huang C, Ma W, Ding M, Bowden GT, Dong Z (1997) Direct evidence for an important role of sphingomyelinase in ultraviolet-induced activation of c-Jun N-terminal kinase. J Biol Chem 272:27753–27757
Huang C, Ma WY, Dawson MI, Rincon M, Flavell RA, Dong Z (1997) Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid. Proc Natl Acad Sci USA 94:5826–5830
Huang C, Ma WY, Hanenberger D, Cleary MP, Bowden GT, Dong Z (1997) Inhibition of ultraviolet B-induced activator protein-1 (AP-1) activity by aspirin in AP-1-luciferase transgenic mice. J Biol Chem 272:26325–26331
Johnson TM, Dolan OM, Hamilton TA, Lu MC, Swanson NA, Lowe L (1998) Clinical and histologic trends of melanoma. J Am Acad Dermatol 38:681–686
Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, Leffell DJ, Tarone RE, Brash DE (1996) Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci USA 93:14025–14029
Karagas MR, Stukel TA, Greenberg ER, Baron JA, Mott LA, Stern RS (1992) Risk of subse quent basal cell carcinoma and squamous cell carcinoma of the skin among pati ents with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 267:3305–3310
Kubba AK (1999) Non steroidal anti-inflammatory drugs and colorectal cancer: is there a way forward? Eur J Cancer 35:892–901
Kubo Y, Urano Y, Yoshimoto K, lwahana H, Fukuhara K, Arase S, Itakura M (1994) p53 gene mutations in human skin cancers and precancerous lesions: comparison with immunohistochemical analysis. J Invest Dermatol 102:440–444
Kuflik AS, Schwartz RA (1994) Actinic keratosis and squamous cell carcinoma. Am Fam Physician 49:817–820
Kuroda Y, Hara Y (1999) Antimutagenic and anticarcinogenic activity of tea polyphenols. Mutat Res 436:69–97
Kwa RE, Campana K, Moy RL (1992) Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol 26:1–26
Leffell DJ (2000) The scientific basis of skin cancer. J Am Acad Dermatol 42:18–22
Levine N (1998) Role of retinoids in skin cancer treatment and prevention. J Am Acad Dermatol 39:S62–S66
Li JJ, Dong Z, Dawson MI, Colburn NH (1996) Inhibition of tumor promoter-induced transformation by retinoids that transrepress AP-l without transactivating retinoic acid response element. Cancer Res 56:483–489
Liang YC, Lin-Shiau SY, Chen CF, Lin JK (1997) Suppression of extracellular signals and cell proliferation through EGF receptor binding by (−)-epigallocatechin gallate in human A431 epidermoid carcinoma cells. J Cell Biochem 67:55–65
Lin JK, Liang YC, Lin-Shiau SY (1999) Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade. Biochem Pharmacol 58:911–915
Lippman SM, Lee JJ, Sabichi AL (1998) Cancer chemoprevention: progres s and promise. J Natl Cancer Inst 90:1514–1528
Lippman SM, Lotan R (2000) Advances in the development of retinoids as chemopreventive agents. J Nutr 130:479S–482S
Lotan R (1996) Retinoids in cancer chemoprevention. FASEB J 10:1031–1039
Ma WY, Huang C, Dong Z (1998) Inhibition of ultraviolet C irradiation-induced AP-1 activity by aspirin is through inhibition of JNKs but not erks or P38 MAP kinase. Int J Oncol 12:565–568
Marks R (1990) Solar keratosis. Br J Dermatol 122[Supp135]:49–60
Marks R (1995) An overview of skin cancers. Incidence and causation. Cancer 75:607–612
Marks R, Rennie G, Selwood TS (1988) Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1:795–797
Matsui MS, DeLeo VA (1995) Photo carcinogenesis by ultraviolet A and B. In: Mukhtar H (ed) Skin cancer: mechanisms and human relevance. CRCPress, Boca Raton, pp 21–30
McNutt NS, Saenz-Santamaria C, Volkenandt M, Shea CR, Albino AP (1991) Abnormalities of p53 protein expression in cutaneous disorders. Arch Dermatol 130:225–232
Mestre JR, Subbaramaiah K, Sacks PG, Schantz SP, Tanabe T, Inoue H, Dannenberg AJ (1997) Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells. Cancer Res 57:2890–2895
Mestre JR, Subbaramaiah K, Sacks PG, Schantz SP, Tanabe T, Inoue H, Dannenberg AJ (1997) Retinoids suppress phorbol ester-mediated induction of cydooxygenase-2. Cancer Res 57:1081–1085
Meyskens FLJr, Edwards L, Levine NS (1986) Role of topical tretinoin in melanoma and dysplastic nevi. J Am Acad Dermatol 15:822–825
Meyskens FLJr, Gerner EW (1999) Development of difluoromethylornithine (DFMO) as a chemoprevention agent. Clin Cancer Res 5:945–951
Moles JP, Moyret C, Guillot B, Jeanteur P, Guilhou JJ, Theillet C, Basset-Seguin N (1993) p53 gene mutations in human epithelial skin cancers. Oncogene 8:583–588
Moller R, Reymann F, Hou-Iensen K (1979) Metastases in dermatological patients with squamous cell carcinoma. Arch Dermatol 115:703–705
Mukhtar H, Ahmad N (1999) Green tea in chemoprevention of cancer. Toxicol Sci 52:111–117
Mukhtar H, Katiyar SK, Agarwal R (1994) Green tea and skin — anticarcinogenic effects. J Invest Dermatol 102:3–7
Nagano T, Ueda M, Ichihashi M (1993) Expression of p53 protein is an early event in ultraviolet light-induced cutaneous squamous cell carcinogenesis. Arch Dermatol 129:1157–1161
Nataraj AJ, Trent JC2nd, Ananthaswamy HN (1995) p53 gene mutations and photocarcino genesis. Photochem Photobiol 62:218–230
National Cancer Institute, National Institutes of Health, Public Health Service, u.s. Department of Health and Human Services (2001) Cancer Progress Report 2001 (http://progressreport.cancer.gov)
Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Neldner KH (1995) High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 131:170–175
Nelson MA, Einspahr JG, Alberts DS, Balfour CA, Wymer JA, Welch KL, Salasche SJ, Bangert JL, Grogan TM, Bozzo PO (1994) Analysis of the p53 gene in human precancerous actinic keratosis lesions and squamous cell cancers. Cancer Lett 85:23–29
Nicholson RC, Mader S, Nagpal S, Leid M, Rochette-Egly C, Chambon P (1990) Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO J 9:4443–4454
Niles RM (2000) Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 16:1084–1089
Nomura M, Ma WY, Huang C, Yang CS, Bowden GT, Miyamoto K, Dong Z (2000) Inhibition of ultraviolet B-induced AP-l activation by theaflavins from black tea. Mol Carcinog 28:148–155
Pegg AE, Madhubala R, Kameji T, Bergeron RJ (1988) Control of ornithine decarboxylase activity in alpha-difluoromethylornithine-resistant L12l0 cells by polyamines and synthetic analogues. J Biol Chem 263:11008–11014
Pentland AP, Schoggins JW, Scott GA, Khan KN, Han R (1999) Reduction of UV-induced skin tumors in hairless mice by selective COX-2inhibition. Carcinogenesis 20:1939–1944
Pierceall WE, Mukhopadhyay T, Goldberg LH, Ananthaswamy HN (1991) Mutations in the p53 tumor suppressor gene in human cutaneous squamous cell carcinomas. Mol Carcinog 4:445–449
Preston DS, Stern RS (1992) Nonmelanoma cancers of the skin. N Engl J Med 327:1649–1662
Ren ZP, Hedrum A, Ponten F, Nister M, Ahmadian A, Lundeberg J, Uhlen M, Ponten J (1996) Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes. Oncogene 12:765–773
Ro YS, Cooper PN, Lee JA, Quinn AG, Harrison D, Lane D, Horne CH, Rees JL, Angus B (1993) p53 protein expression in benign and malignant skin tumours. Br J Dermatol 128:237–241
Salasche SJ (2000) Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42:S4–S7
Schule R, Rangarajan P, Yang N, Kliewer S, Ransone LJ, Bolado J, Verma IM, Evans RM. (1991) Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci USA 88:6092–6096
Shea CR, McNutt NS, Volkenandt M, Lugo J, Prioleau PG, Albino AP (1992) Overexpression of p53 protein in basal cell carcinomas of human skin. Am J Pathol 141:25–29
Sim CS, Slater SD, McKee PH (1991) Mutant p53 protein is express ion in solar keratosis: an immunohistochemical study. J Cutan Pathol 19:302–308
Sim CS, Slater SD, McKee PH (1992) Mutant p53 protein is expressed in Bowen’s disease. Am J Dermatopathol 14:195–199
Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182
Stam-Posthuma JJ, Vink J, le Cessie S, Bruijn JA, Bergman W, Pavel S (1998) Effect of topical tretinoin under occlusion on atypical naevi. Melanoma Res 8:539–548
Taguchi M, Watanabe S, Yashima K, Murakami Y, Sekiya T, Ikeda S (1994) Aberrations of the tumor suppressor p53 gene and p53 protein in solar keratosis in human skin. J Invest Dermatol 103:500–503
Takigawa M, Verma AK, Simsiman RC, Boutwell RK (1983) Inhibition of mouse skin tumor promotion and of promoter-stimulated epidermal polyamine biosynthesis by alpha-difluoromethylornithine. Cancer Res 43:3732–3738
Tang Q, Chen W, Gonzales MS, Finch J, Inoue H, Bowden GT (2001) Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes. Oncogene 20:5164–5172
Tang Q, Gonzales M, Inoue H, Bowden GT (2001) Roles of Akt and glycogen synthase kinase 3beta in the ultraviolet B induction of cyclooxygenase-2 transcription in human keratinocytes. Cancer Res 61:4329–4332
Urano Y, Asano T, Yoshimoto K, Iwahana H, Kubo Y, Kato S, Sasaki S, Takeuchi N, Uchida N, Nakanishi H (1995) Frequent p53 accumulation in the chronically sun-exposed epidermis and clonal expansion of p53 mutant cells in the epidermis adjacent to basal cell carcinoma. J Invest Dermatol 104:928–932
Urano Y, Oura H, Sakaki A, Nagae H, Matsumoto K, Fukuhara K, Nagae T, Arase S, Ninomiya Y, Nakanishi H (1992) Immunohistological analysis of p53 expression in human skin tumors. J Dermatol Sci 4:69–75
Weeks CE, Herrmann AL, Nelson FR, Slaga TJ (1982) alpha-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. Proc Natl Acad Sci USA 79:6028–6032
Xie W, Herschman HR (1995) v-src induces prostaglandin synthase 2-gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem 270:27622–27628
Yang CS, Wang ZY (1993) Tea and cancer. J Natl Cancer Inst 85:1038–1049
Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R, Colburn N (1999) Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA 96:9827–9832
Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T, Brash DE (1994) Sunburn and p53 in the onset of skin cancer. Nature 372:773–776
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Einspahr, J.G., Bowden, G.T., Alberts, D.S. (2003). Skin Cancer Chemoprevention: Strategies to Save Our Skin. In: Senn, HJ., Morant, R. (eds) Tumor Prevention and Genetics. Recent Results in Cancer Research, vol 163. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55647-0_14
Download citation
DOI: https://doi.org/10.1007/978-3-642-55647-0_14
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-62892-4
Online ISBN: 978-3-642-55647-0
eBook Packages: Springer Book Archive