Archives of Dermatological Research

, Volume 299, Issue 8, pp 373–379 | Cite as

Regulation of the extracellular matrix remodeling by lutein in dermal fibroblasts, melanoma cells, and ultraviolet radiation exposed fibroblasts

  • Neena PhilipsEmail author
  • Thomas Keller
  • Cynthia Hendrix
  • Shannon Hamilton
  • Rosemarie Arena
  • Marvin Tuason
  • Salvador Gonzalez
Original Paper


With aging and cancer there is increased expression or activity of matrix metalloproteinases (MMPs) that degrade and remodel the structural extracellular matrix (ECM). In addition, exposure of skin to ultraviolet (UV) radiation (photoaging) leads to loss of cell viability, membrane damage, and deposition of excessive elastotic material. Lutein has antioxidant, anti-inflammatory, photoprotective, and anti-carcinogenic properties. The goal of this research was to investigate lutein’s anti-aging and anti-carcinogenic effects via the regulation of the extracellular matrix remodeling. To this purpose, the effects of lutein on the expression of MMPs and their inhibitors (TIMPs, tissue inhibitors of metalloproteinases) in dermal fibroblasts (intrinsic aging) and melanoma cells were examined. Further, for lutein’s photoprotective effects, the regulation of cell viability, membrane integrity, and elastin expression in the non-irradiated, and UVA or UVB radiation exposed fibroblasts were analyzed. Lutein significantly inhibited MMP-1 expression, transcriptionally, and MMP-2 protein levels in dermal fibroblasts, without altering TIMPs expression. It significantly inhibited MMP-1 expression in melanoma cells while stimulating TIMP-2. Lutein did not alter fibroblast or melanoma cell viability or membrane integrity. In ultraviolet radiation exposed fibroblasts, lutein improved cell viability, membrane integrity and inhibited elastin expression, though more significantly in the UVB exposed fibroblasts. In summary, the mechanism to lutein’s anti-aging and anti-carcinogenic effects include the inhibition of MMP to TIMP ratio in dermal fibroblasts and melanoma cells, and the inhibition of cell loss, membrane damage and elastin expression in ultraviolet radiation exposed fibroblasts.


Lutein Ultraviolet radiation Extracellular matrix Melanoma Fibroblasts 



Funding was provided partly by the Departments of Biology and Chemistry/Biochemistry of Georgian Court University, Lakewood, NJ.


  1. Astner S, Wu A, Chen J, Philips N, Rius-Diaz F, Parrado C, Mihm MC, Goukassian DA, Pathak MA, and González, S (2007) Dietary lutein/zeaxanthin reduces photoaging and photocarcinogenesis in chronically UVB irradiated SKH-1 hairless mice. Skin Pharmacol Physiol (in press)Google Scholar
  2. Beatty S, Boulton M, Henson D, Koh HH, Murray IJ (1999) Macular pigment and age related macular degeneration. Br J Ophthalmol 83:867–877PubMedCrossRefGoogle Scholar
  3. Bernd A, Ramirez-Bosca A, Huber H, Diaz-Alperi J, Thaci D, Sewell A Auintanilla-Almagro E, Holzmann H (1995). In vitro studies on the immunomodulating effects of poloypodium leucotomos extract on human leukocyte fractions. Arzneim-Forsch Drug Res 45:901–904Google Scholar
  4. Broekmans WMR, Berendschot TTJM, Klöpping-Ketelaars IAA, de Vries AJ, Goldbohm RA, Tjiburg BM (2002) Macular pigment density in relation to serum and adipose tissue concentrations of lutein and serum concentrations of zeaxanthin. Am J Clin Nutr 76:595–603PubMedGoogle Scholar
  5. Clark LC, Combs GF, Turnbull BW, Slate EH, Chalker DK, Chow J et al (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276:1957–1963PubMedCrossRefGoogle Scholar
  6. Dalle Carbonare M, Pathak MA (1992) Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B 14:105–124PubMedCrossRefGoogle Scholar
  7. Damiani E, Rosati L, Castagna R, Carloni P, Greci L (2006) Changes in ultraviolet absorbance and hence in protective efficacy against lipid peroxidation of organic sunscreens after UVA irradiation. J Photochem Photobiol B 82:204–213PubMedCrossRefGoogle Scholar
  8. Darr D, Pinnell SR (1997) Reactive oxygen species and antioxidants protection in photodermatology. Sunscreens. Lowe NJ, Shaat NA, Pathak MA (eds) Marcel Dekker, New York, pp 155–173Google Scholar
  9. Dickson RB, Lippman ME (1995). Growth factors in breast cancer. Endocr Rev 16:559–589PubMedCrossRefGoogle Scholar
  10. Djavaheri-Mergny M, Mergny JL, Bertrand F, Santus R, Maziere C, Dubertret L, Maziere JC (1996). Ultraviolet-A induces activation of AP-1 in cultured human keratinocytes. FEBS Lett 384:92–96PubMedCrossRefGoogle Scholar
  11. Dwyer JH, Mohamed N, Dwyer KM, Kholood H, Sun P, Shircore A, Hama- Levy S (2001) Oxygenated carotenoid lutein and progression of early atherosclerosis. The Los Angeles atherosclerosis study. Circulation 103:2922–2927PubMedGoogle Scholar
  12. Fitzpatrick TB (1988) The validity and practicality of sun reactive skin type I-VI. Arch Dermatol 124:869–871PubMedCrossRefGoogle Scholar
  13. Giacomoni PU, Rein G (2001) Factors of skin ageing share common mechanisms. Biogerontology 2:219–229PubMedCrossRefGoogle Scholar
  14. González S, Moran M, Kochevar IE (1999) Chronic photodamage in skin of mast cell-deficient mice. Photochem Photobiol 70:248–253PubMedCrossRefGoogle Scholar
  15. González S, Pathak MA (1996) Inhibition of ultraviolet-induced formation of reactive oxygen species, lipid peroxidation, erythema, and skin photosensitization by Polypodium leucotomos. Photodermatol Photoimmunol Photomed 12:45–56PubMedGoogle Scholar
  16. Gonzalez S, Astner S, An W, Goukassian D, Pathak MA (2003) Dietary lutein/zeaxanthin decreases ultraviolet B-induced epidermal hyperproliferation and acute inflammation in hairless mice. J Invest Dermatol 121:399–405PubMedCrossRefGoogle Scholar
  17. Ingram D (1994) Diet and subsequent survival in women with breast cancer. Br J Cancer 69:71–80Google Scholar
  18. Jain M, Miller AB, To T (1994) Premorbid diet and the prognosis of women with breast cancer. J Natl Cancer Inst 86:1390–1397PubMedCrossRefGoogle Scholar
  19. Janczyk A, Garcia-Lopez MA, Penas P, Alonso-Lebrero JL, Benedicto I, Lopez-Cabrera, Gonzalez S (2007) A Polypodium leucotomos extract (PL) inhibits solar-simulated radiation-induced TNF-a and iNOS expression, transcriptional activation and apoptosis. Exp Dermatol (in press)Google Scholar
  20. Kao RT, Stern R (1986). Collagenases in human breast carcinoma cell lines. Cancer Res 46:1349–1354PubMedGoogle Scholar
  21. Khachik F, Beecher GR, Smith JC (1995) Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer. J Cell Biochem 22:236–246CrossRefGoogle Scholar
  22. Kligman AM (1988) Preventing, delaying, and repairing photoaged skin. Cutis 41:419–420PubMedGoogle Scholar
  23. Kligman LH (1986) Photoaging. Manifestations, prevention, and treatment. Dermatol Clin 4:517–528PubMedGoogle Scholar
  24. Krinsky NI (1994) Carotenoids and cancer: basic research studies. In: Frei B (ed) National antioxidants in human health and disease. Academic, San Diego, pp 239–261Google Scholar
  25. Kozuki Y, Miura Y, Yagasaki K (2000) Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture. Cancer Lett 151(1):111–115PubMedCrossRefGoogle Scholar
  26. Mc Bride, Preston PD, Loeb LA (1991) Mutagenic spectrum resulting from DNA damage by oxygen radicals. Biochemistry 30:207–213CrossRefGoogle Scholar
  27. Millen AE, Tucker MA, Hartge P, Halpern A, Elder DE, Guerry D 4th, Holly EA, Sagebiel RW, Potischman N (2004) Diet and melanoma in a case-control study. Cancer Epidemiol Biomarkers Prev 13(6):1042–1051PubMedGoogle Scholar
  28. Moysan A, Marquis I, Gaboriau F, Santus R, Dubertret L, Morliere P (1993) Ultraviolet A-induced lipid peroxidation and antioxidant defense systems in cultured human skin fibroblasts. J Invest Dermatol 100:692–698PubMedCrossRefGoogle Scholar
  29. Narisawa T, Fukaura Y, Hasebe M, Michiko I, Aizawa R, Murakoshi M, Uemura S, Khachik F, Nishino H (1996) Inhibitory effects of natural carotenoids, ol-carotene, B-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats. Cancer Lett 106:137–142CrossRefGoogle Scholar
  30. Oba A, Edwards C (2006) Relationships between changes in mechanical properties of the skin, wrinkling, and destruction of dermal collagen fiber bundles caused by photoaging. Skin Res Technol 4:283–288CrossRefGoogle Scholar
  31. Oh JH, Kim A, Park JM, Kim SH, Chung AS (2006) Ultraviolet B-induced matrix metalloproteinase-1 and -3 secretions are mediated via PTEN/Akt pathway in human dermal fibroblasts. J Cell Physiol 3:775–785CrossRefGoogle Scholar
  32. Pasquali-Ronchetti I, Baccarani-Contri M (1997) Elastic fiber during development and aging. Microsc Res Tech 38:428–435PubMedCrossRefGoogle Scholar
  33. Petersen M, Hamilton T, Li HL (1995). Regulation and inhibition of collagenase expression by long-wavelength ultraviolet radiation in cultured human skin fibroblasts. Photochem Photobiol 62:444–448PubMedGoogle Scholar
  34. Petersen MJ, Hansen C, Craig S (1992). Ultraviolet A irradiation stimulates collagenase production in cultured human fibroblasts. J Invest Dermatol 99:440–444PubMedCrossRefGoogle Scholar
  35. Philips N, Burchill D, O’Donoghue D, Keller T, Gonzalez S (2004) Identification of benzene metabolites in dermal fibroblasts: regulation of cell viability, apoptosis, lipid peroxidation, and expression of MMP-1 and elastin by benzene metabolites. Skin Pharmacol Physiol 17:147–152PubMedCrossRefGoogle Scholar
  36. Philips N, Devaney J (2003) Beneficial regulation of type I collagen and matrixmetalloproteinase-1 expression by estrogen, progesterone, and its combination in skin fibroblasts. J Am Aging Association 26:59–62Google Scholar
  37. Philips N, McFadden K (2004) Inhibition of transforming growth factor-beta and matrix metalloproteinases by estrogen, and prolactin in breast cancer cells. Cancer Lett 206:63–68PubMedCrossRefGoogle Scholar
  38. Philips N, Smith J, Keller T, Gonzalez S (2003) Predominant effects of Polypodium leucotomos on membrane integrity, lipid peroxidation, and expression of elastin and matrixmetalloproteinase-1 in ultraviolet radiation exposed fibroblasts, and keratinocytes. J Dermatol Sci 32:1–9PubMedCrossRefGoogle Scholar
  39. Philips N (2003) An anti TGF-b increased the expression of transforming growth factor-b, matrix metallproteinase-1, and elastin, and its effects were antagonized by ultraviolet radiation in epidermal keratinocytes. J Dermatol Sci 33:177–179PubMedCrossRefGoogle Scholar
  40. Pratt S (1990) Dietary prevention of age-related macular degeneration. J Am Optom Assoc 70:39–47Google Scholar
  41. Preston D, Stern RS (1992) Non melanoma skin cancer of the skin. N Engl J Med 327:1649–1662PubMedCrossRefGoogle Scholar
  42. Scharffetter-Kochanek K, Brenneisen P, Wenk J, Herrmann G, Ma W, Kuhr L, Keewes C, Wlaschek M (2000). Photoaging of the skin from phenotype to mechanisms. Exp Gerontol 35:307–316PubMedCrossRefGoogle Scholar
  43. Scharffetter K, Wlaschek M, Hogg A, Bolsen K, Schothorst A, Goerz G, Krieg T, Plewig G (1991). UVA irradiation induces collagenase in human dermal fibroblasts in vitro and in vivo. Arch Dermatol Res 283:506–511PubMedCrossRefGoogle Scholar
  44. Schwartz E, Gelfand JM, Mauch JC, Kligman LH (1998) Generation of a tropoelastin mRNA variant by alternative polyadenylation site selection in sun-damaged human skin and ultraviolet B-irradiated fibroblasts. Biochem Biophys Res Commun 246:217–221PubMedCrossRefGoogle Scholar
  45. Slattery ML, Benson J, Curtin K, Khe-NI M, Schaeffer D, Potter JD (2000) Carotenoids and colon cancer. Am J Clin Nutr 71:575–582PubMedGoogle Scholar
  46. Snodderly DM (1995) Evidence for protection against age-related macula degeneration by carotenoids and antioxidant vitamins. Am J Clin Nutr 62:1448S–1461SPubMedGoogle Scholar
  47. Svobodova A, Walterova D, Vostalova (2006) Ultraviolet light induced alteration to the skin. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 150:25–38PubMedGoogle Scholar
  48. Talvensaari-Mattila A, Paakko P, Hoyhtya M, Blance-Sequeiros G, Turpeenniemi-Hujanen T (1998). Matrix metalloproteinase-2 immunoreactive protein: a marker of aggressiveness in breast carcinoma. Cancer 83:1153–1162PubMedCrossRefGoogle Scholar
  49. Toyoda M, Bhawan J (1995) Electron-microscopic observations of cutaneous photoaging versus intrinsic aging. J Geriatr Dermatol 3:131–143Google Scholar
  50. Tupet A, Lebreton-De Coster C, Dubertret L, Bernard C (1999) Low doses of ultraviolet A irradiation stimulate adhesion of human dermal fibroblasts by integrins in a protein kinase C-dependent pathway. J Photochem Photobiol 49:150–155CrossRefGoogle Scholar
  51. Wingerath T, Sies H, Stahl W (1998) Xanthophyll esters in human skin. Arch Biochem Biophys 355:271–274PubMedCrossRefGoogle Scholar
  52. Werth VP, Williams KJ, Fisher EA, Bashir M, Rosenbloom J, Shi X (1997) UVB irradiation alters cellular responses to cytokines: role in extracellular matrix gene expression. J Invest Dermatol 108:290–294PubMedCrossRefGoogle Scholar
  53. Wlaschek M, Briviba K, Stricklin GP, Sies H, Scharffetter-Kochanek K (1995). Singlet oxygen may mediate the ultraviolet A-induced synthesis of interstitial collagenase. J Invest Dermatol 104:194–198 PubMedCrossRefGoogle Scholar
  54. Wlaschek M, Heinen G, Poswig A, Schwarz A, Krieg T, Scharffetter-Kochanek K (1994). UVA-induced autocrine stimulation of fibroblast-derived collagenase/MMP-1 by interrelated loops of interleukin-1 and interleukin-6. Photochem Photobiol 59:550–556PubMedGoogle Scholar
  55. Wlaschek M, Wenk J, Brenneisen P, Briviba K, Schwarz A, Sies H, Scharffetter-Kochanek K (1997). Singlet oxygen is an early intermediate in cytokine-dependent ultraviolet-A induction of interstitial collagenase in human dermal fibroblasts in vitro. FEBS Lett 413:539–542CrossRefGoogle Scholar
  56. Zeng G, McCue H, Mastrangelo L, Millis A (1996) Endogenous TGF-β activity is modified during cellular aging: effects on metalloproteinase and TIMP-l expression. Exp Cell Res 228:271–276PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Neena Philips
    • 1
    • 2
    • 5
    Email author
  • Thomas Keller
    • 1
  • Cynthia Hendrix
    • 1
  • Shannon Hamilton
    • 1
  • Rosemarie Arena
    • 2
  • Marvin Tuason
    • 2
  • Salvador Gonzalez
    • 3
    • 4
  1. 1.School of Science and MathematicsGeorgian Court UniversityLakewoodUSA
  2. 2.School of Natural SciencesFairleigh Dickinson UniversityTeaneckUSA
  3. 3.DermatologyMassachussets General Hospital, Harvard Medical SchoolBostonUSA
  4. 4.DermatologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  5. 5.University College, H-DH4-03TeaneckUSA

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