European Journal of Cancer
Volume 41, Issue 13 , Pages 1969-1979 , September 2005

Mechanisms and preclinical efficacy of silibinin in preventing skin cancer

  • Rana P. Singh

      Affiliations

    • Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO 80262, United States
    • ,
  • Rajesh Agarwal

      Affiliations

    • Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO 80262, United States
    • University of Colorado Cancer Center, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, United States
    • Corresponding Author InformationCorresponding author. Tel.: +1 303 315 1381; fax: +1 303 315 6281.

Received 2 March 2005 ,Revised 10 March 2005 ,Accepted 18 March 2005.

References 

  1. Singh RP, Agarwal R. SENCAR mouse skin tumourigenesis model. In:  Teicher BA editors. Tumour models in cancer research. Totowa (NJ): Humana Press; 2001;p. 359–380
  2. Zoumpourlis V, Solakidi S, Papathoma A, et al. Alterations in signal transduction pathways implicated in tumour progression during multistage mouse skin carcinogenesis. Carcinogenesis. 2003;24:1159–1165
  3. Harris RB, Alberts DS. Strategies for skin cancer prevention. Int J Dermatol. 2004;43:243–251
  4. McKenzie R, Connor B, Bodeker G. Increased summertime UV radiation in New Zealand in response to ozone loss. Science. 1999;285:1709–1711
  5. Bowden GT. Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling. Nat Rev Cancer. 2004;4:23–35
  6. Gloster HM, Brodland DG. The epidemiology of skin cancer. Dermatol Surg. 1996;22:217–226
  7. Matsui MS, DeLeo VA. Photocarcinogenesis by ultraviolet A and B. In:  Mukhtar H editors. Skin cancer: mechanisms and human relevance. Boca Raton (FL): CRC Press; 1995;p. 21–30
  8. Kanjilal S, Ananthaswamy HN. In:  Weber R,  Miller M,  Goepfert H editor. Basal and squamous cell skin cancers of the head and neck. Baltimore: Williams and Wilkins; 1996;p. 25–26
  9. Pourzand C, Tyrrell RM. Apoptosis, the role of oxidative stress and the example of solar UV radiation. Photochem Photobiol. 1999;70:380–390
  10. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372:773–776
  11. Gilchrest BA. A review of skin ageing and its medical therapy. Br J Dermatol. 1996;135:867–875
  12. Cruz JR, Leverkus PDM, Dougherty I, et al. Thymidine dinucleotides inhibit contact hypersensitivity and activate the gene for tumour necrosis factor alpha1. J Invest Dermatol. 2000;114:253–258
  13. Kulms D, Schwarz T. Molecular mechanisms of UV-induced apoptosis. Photodermatol Photoimmunol Photomed. 2000;16:195–201
  14. Matsumura Y, Ananthaswamy HN. Toxic effects of ultraviolet radiation on the skin. Toxicol Appl Pharmacol. 2004;195:298–308
  15. Chin L. The genetics of melanoma: lessons from mouse and man. Nat Rev Cancer. 2003;3:559–570
  16. Wolf P, Donawho CK, Kripke ML. Effect of sunscreens on UV radiation-induced enhancement of melanoma growth in mice. J Nat Cancer Inst. 1994;86:99–105
  17. Pinnell SR. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol. 2003;48:1–19
  18. Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci USA. 1995;92:5258–5265
  19. Potter JD. Cancer prevention: epidemiology and experiment. Cancer Lett. 1997;114:7–9
  20. Sporn MB, Suh N. Chemoprevention: an essential approach in controlling cancer. Nat Rev Cancer. 2002;2:537–543
  21. Bickers DR, Athar M. Novel approaches to chemoprevention of skin cancer. J Dermatol. 2000;27:691–695
  22. Bode AM, Dong Z. Signal transduction pathways: targets for chemoprevention of skin cancer. Lancet Oncol. 2000;1:181–188
  23. Hong JT, Kim EJ, Ahn KS, et al. Inhibitory effect of glycolic acid on ultraviolet-induced skin tumourigenesis in SKH-1 hairless mice and its mechanism of action. Mol Carcinog. 2001;31:152–160
  24. Lu YP, Lou YR, Lin Y, et al. Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): relationship to decreased tissue fat. Cancer Res. 2001;61:5002–5009
  25. Conney AH. Tailoring cancer chemoprevention regimens to the individual. J Cell Biochem. 2004;91:277–286
  26. Huang MT, Xie JG, Wang ZY, et al. Effects of tea, decaffeinated tea, and caffeine on UVB light-induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically important constituent of tea. Cancer Res. 1997;57:2623–2629
  27. Katiyar SK, Korman NJ, Mukhtar H, et al. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst. 1997;89:56–66
  28. Lu YP, Lou YR, Xie JG, et al. Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumours in mice. Proc Natl Acad Sci USA. 2002;99:12455–12460
  29. Mallikarjuna G, Dhanalakshmi S, Singh RP, et al. Silibinin protects against photocarcinogenesis via modulation of cell cycle regulators, mitogen-activated protein kinases, and Akt signalling. Cancer Res. 2004;64:6349–6356
  30. Zhao J, Sharma Y, Agarwal R. A Flavonoid antioxidant, silymarin, affords significant inhibition against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interlukin-1α expression in SENCAR mouse epidermis: Implications in the prevention of stage I tumour. Mol Carcinog. 1999;26:321–333
  31. Lahiri-Chatterjee M, Katiyar SK, Mohan RR, et al. A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumour promotion in the SENCAR mouse skin tumourigenesis model. Cancer Res. 1999;59:622–632
  32. Singh RP, Tyagi AK, Zhao J, et al. Silymarin inhibits growth and causes regression of established skin tumours in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis. 2002;23:499–510
  33. Singh RP, Agarwal R. Flavonoid antioxidant silymarin and skin cancer. Antioxid Redox Signal. 2002;4:655–663
  34. Blumenthal M. Herbs sales down 3% in mass market retail stores: sales in natural food stores still growing, but at lower rate. HerbalGram. 2000;49:68
  35. Wagner H, Diesel P, Seitz M. Chemistry and analysis of silymarin from Silybum marianum (L) Gaertn. Arzneimittelforsch. 1974;24:466–471
  36. Wellington K, Jarwis B. Silymarin: a review of its clinical properties in the management of hepatic disorders. BioDrugs. 2001;15:465–489
  37. Trost W, Halbach G. Anti-phalloidine and anti-alpha-amanitine action of silybin in comparison with compounds similar to structural parts of silybin. Experientia. 1978;34:1051–1052
  38. Trinchet JC, Coste T, Levy VG, et al. Treatment of alcoholic hepatitis with silymarin. A double-blind comparative study in 116 patients. Gastroenterol Clin Biol. 1989;13:120–124
  39. Pares A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol. 1998;28:615–621
  40. Vogel G, Trost W, Braatz R. Studies on the pharmacodynamics, including site and mode of action, of silymarin: the antihepatotoxic principle from Silybum marianum (L) Gaertn. Arzneimittelforsch. 1975;25:82–89
  41. Singh RP, Dhanalakshmi S, Tyagi AK, et al. Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res. 2002;62:3063–3069
  42. Agarwal C, Singh RP, Dhanalakshmi S, et al. Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene. 2003;22:8271–8282
  43. Bhatia N, Zhao J, Wolf DM, et al. Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett. 1999;147:77–84
  44. Singh RP, Agarwal R. Prostate cancer prevention by silibinin. Curr Cancer Drug Targets. 2004;4:1–11
  45. Tyagi AK, Agarwal C, Singh RP, et al. Silibinin down-regulates survivin protein and mRNA expression and causes caspases activation and apoptosis in human bladder transitional-cell papillomas RT4 cells. Biochem Biophys Res Commun. 2003;312:1178–1184
  46. Sharma G, Singh RP, Chan DC, et al. Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells. Anticancer Res. 2003;23:2649–2655
  47. Kohno H, Tanaka T, Kawabata K, et al. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer. 2002;101:461–468
  48. Singh RP, Mallikarjuna GU, Sharma G, et al. Oral silibinin inhibits lung tumour growth in athymic nude mice and forms a novel chemocombination with doxorubicin targeting nuclear factor kappaB-mediated inducible chemoresistance. Clin Cancer Res. 2004;10:8641–8647
  49. Zi X, Mukhtar H, Agarwal R. Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumour promoter TNFα. Biochem Biophys Res Commun. 1997;239:334–339
  50. Zhao J, Lahiri-Chatterjee M, Sharma Y, et al. Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumour promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis. 2000;21:811–816
  51. Tornaletti S, Pfeifer GP. UV damage and repair mechanisms in mammalian cells. Bioessays. 1996;18:221–228
  52. Lu YP, Lou YR, Yen P, et al. Time course for early adaptive responses to ultraviolet B light in the epidermis of SKH-1 mice. Cancer Res. 1999;59:4591–4602
  53. Dhanalakshmi S, Mallikarjuna GU, Singh RP, et al. Silibinin prevents ultraviolet radiation-caused skin damages in SKH-1 hairless mice via a decrease in thymine dimer positive cells and an up-regulation of p53–p21/Cip1 in epidermis. Carcinogenesis. 2004;25:1459–1465
  54. Mallikarjuna G, Dhanalakshmi S, Singh RP, et al. Dietary feeding of silibinin prevents early biomarkers of ultraviolet B radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Cancer Epidemiol Biomark Prev. 2005;14:1344–1349
  55. Mukhtar H, Agarwal R. Skin cancer chemoprevention. J Invest Dermatol Sym Proc. 1996;1:209–214
  56. Fischer SM, Slaga TJ. Arachidonic acid metabolism and tumour promotion. Boston: Martinus Nijhoff Publishing; 1985;pp. 1–263
  57. DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;54:63–128
  58. Li G, Ho VC. p53-dependent DNA repair and apoptosis respond differently to high- and low-dose ultraviolet radiation. Br J Dermatol. 1998;139:3–10
  59. Ouhtit A, Muller HK, Davis DW, et al. Temporal events in skin injury and the early adaptive responses in ultraviolet-irradiated mouse skin. Am J Pathol. 2000;156:201–207
  60. Ramzi ST, Maruno M, Khaskhely NM, et al. An assessment of the malignant potential of actinic keratoses and Bowen’s disease: p53 and PCNA expression pattern correlate with the number of desmosomes. J Dermatol. 2002;29:562–572
  61. Mass P, Hoffmann K, Gambichler T, et al. Premature keratinocyte death and expression of marker proteins of apoptosis in human skin after UVB exposure. Arch Dermatol Res. 2003;295:71–79
  62. Liebermann DA, Hoffman B, Steinman RA. Molecular controls of growth arrest and apoptosis: p53-dependent and independent pathways. Oncogene. 1995;11:199–210
  63. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310
  64. Bode AM, Dong Z. Post-translational modification of p53 in tumourigenesis. Nat Rev Cancer. 2004;4:793–805
  65. Huang LC, Clarkin KC, Wahl GM. Sensitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest. Proc Natl Acad Sci USA. 1996;93:4827–4832
  66. Mullauer L, Gruber P, Sebinger D, et al. Mutations in apoptosis genes: a pathogenetic factor for human disease. Mutat Res. 2001;488:211–231
  67. Fuchs SY, Adler V, Buschmann T, et al. Mdm2 association with p53 targets its ubiquitination. Oncogene. 1998;17:2543–2547
  68. Olivier M, Hussain SP, Caron de Fromentel C, et al. TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ. 2004;157:247–270
  69. Dhanalakshmi S, Agarwal C, Singh RP, et al. Silibinin up-regulates DNA-PK-dependent p53 activation to enhance UVB-induced apoptosis in mouse epithelial JB6 cells. J Biol Chem. 2005;280:20375–20383
  70. Dhanalakshmi S, Mallikarjuna GU, Singh RP, et al. Dual-efficacy of silibinin in protecting or enhancing ultraviolet B radiation-caused apoptosis in human immortalized keratinocyte HaCaT cells. Carcinogenesis. 2004;25:99–106
  71. Chen X, Ko LJ, Jayaraman L, et al. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumour cells. Genes Dev. 1996;10:2438–2451
  72. Seger R, Krebs EG. The MAPK signalling cascade. FASEB J. 1995;9:726–735
  73. Chen W, Bowden GT. Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes. Oncogene. 1999;18:7469–7476
  74. Bode AM, Dong Z. Mitogen-activated protein kinase activation in UV-induced signal transduction. Sci STKE. 2003;2003:1–15
  75. Boldt S, Weidle UH, Kolch W. The role of MAPK pathways in the action of chemotherapeutic drugs. Carcinogenesis. 2002;23:1831–1838
  76. Mallikarjuna G, Dhanalakshmi S, Mohan S, et al. Silibinin inhibits ultraviolet B radiation-induced mitogenic and survival signalling, and associated biological responses in SKH-1 mouse skin. Carcinogenesis, 2005 April 14 [Epub ahead of print].
  77. Cheng M, Sexl V, Sherr CJ, et al. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogenactivated protein kinase kinase (MEK1). Proc Natl Acad Sci USA. 1998;95:1091–1096
  78. Ponten F, Berne B, Ren ZP, et al. Ultraviolet light induces expression of p53 and p21 in human skin: effect of sunscreen and constitutive p21 expression in skin appendages. J Invest Dermatol. 1995;105:402–406
  79. Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer. 2004;4:592–603
  80. Cotton J, Spandau DF. Ultraviolet B-radiation dose influences the induction of apoptosis, and p53 in human keratinocytes. Radiat Res. 1997;147:148–155
  81. Testa JR, Bellacosa A. AKT plays a central role in tumourigenesis. Proc Natl Acad Sci USA. 2001;98:10983–10985
  82. Gottlieb TM, Leal JF, Seger R, et al. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene. 2002;21:1299–1303
  83. Bachelder RE, Ribick MJ, Marchetti A, et al. p53 inhibits alpha 6 beta 4 integrin survival signalling by promoting the caspase 3-dependent cleavage of AKT/PKB. J Cell Biol. 1999;147:1063–1072
  84. Altieri DC. The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med. 2001;7:542–547
  85. Altieri DC. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene. 2003;22:8581–8589
  86. Allen SM, Florell SR, Hanks AN, et al. Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumour progression. Cancer Res. 2003;63:567–572
  87. Morgan DO. Principles of CDK regulation. Nature. 1995;374:131–134
  88. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–1512
  89. Ducoux M, Urbach S, Baldacci G, et al. Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA replication through a conserved p21(Cip1)-like PCNA-binding motif present in the third subunit of human DNA polymerase delta. J Biol Chem. 2001;276:49258–49266
  90. Fotedar R, Bendjennat M, Fotedar A. Role of p21WAF1 in the cellular response to UV. Cell Cycle. 2004;3:134–137
  91. Polyak K, Kato JY, Solomon MJ, et al. p27Kip1, a cyclin–Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994;8:9–22
  92. Friedberg EC. How nucleotide excision repair protects against cancer. Nat Rev Cancer. 2001;1:22–33
  93. Smith ML, Fornace AJ. p53-mediated protective responses to UV irradiation. Proc Natl Acad Sci USA. 1997;94:12255–12257
  94. Kunkel TA, Bebenek K. DNA replication fidelity. Annu Rev Biochem. 2000;69:497–529

PII: S0959-8049(05)00474-0

doi: 10.1016/j.ejca.2005.03.033

European Journal of Cancer
Volume 41, Issue 13 , Pages 1969-1979 , September 2005

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