Skip to main content
Top
Published in: Archives of Dermatological Research 10/2010

01-12-2010 | Original Paper

Suppression of TGF-β1/SMAD pathway and extracellular matrix production in primary keloid fibroblasts by curcuminoids: its potential therapeutic use in the chemoprevention of keloid

Authors: Yi-Chiang Hsu, Ming-Jenn Chen, Ya-Mei Yu, Shun-Yao Ko, Chi-Chang Chang

Published in: Archives of Dermatological Research | Issue 10/2010

Login to get access

Abstract

Keloid is a fibrotic disease characterized by abnormal accumulation of extracellular matrix (ECM) in the dermis. It is a late spreading skin overgrowth and may be considered a plastic surgeon’s nightmare. In nature, curcuminoid is composed of curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (bDMC). Curcuminoids have been found to inhibit fibrosis. However, their role in the synthesis of ECM in the keloid fibroblasts (KFs) has remained unclear. In this series of studies, a total of seven primary KFs cultures were used as the KFs model for investigating the inhibitory effect of curcuminoids on the expression of ECM and TGF-β1. A sensitive and reproducible HPLC method was developed to provide a quantitative analysis on the cellular uptake of curcuminoids onto the KF cells. The level of ECM in the primary KFs was elevated. The elevation of ECM and TGF-β1/p-SMAD-2 level was substantially blocked by the cellular uptake of curcumin in a dose-dependent manner in all the seven primary KFs. The results have led to the conclusion that the excessive production of ECM in the KF cells could be blocked and/or rapidly decreased by curcumin.
Literature
1.
go back to reference Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398PubMed Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398PubMed
2.
go back to reference Ahmad N, Katiyar SK, Mukhtar H (2001) Antioxidants in chemoprevention of skin cancer. Curr Probl Dermatol 29:128–139CrossRefPubMed Ahmad N, Katiyar SK, Mukhtar H (2001) Antioxidants in chemoprevention of skin cancer. Curr Probl Dermatol 29:128–139CrossRefPubMed
3.
go back to reference Albina JE, Mills CD, Henry WL Jr, Caldwell MD (1990) Temporal expression of different pathway of l-arginine metabolism in healing wounds. J Immunol 144:3877–3880PubMed Albina JE, Mills CD, Henry WL Jr, Caldwell MD (1990) Temporal expression of different pathway of l-arginine metabolism in healing wounds. J Immunol 144:3877–3880PubMed
4.
go back to reference Bar-Sela G, Epelbaum R, Schaffer M (2010) Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications. Curr Med Chem 17:190–197CrossRefPubMed Bar-Sela G, Epelbaum R, Schaffer M (2010) Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications. Curr Med Chem 17:190–197CrossRefPubMed
5.
go back to reference España A, Solano T, Quintanilla E (2001) Bleomycin in the treatment of keloids and hypertrophic scars by multiple needle punctures. Dermatol Surg 27:23–27CrossRefPubMed España A, Solano T, Quintanilla E (2001) Bleomycin in the treatment of keloids and hypertrophic scars by multiple needle punctures. Dermatol Surg 27:23–27CrossRefPubMed
6.
go back to reference Hsu YC, Hsiao M, Wang LF, Chien YW, Lee WR (2006) Nitric oxide produced by iNOS is associated with collagen synthesis in keloid scar formation. Nitric Oxide 14:327–334CrossRefPubMed Hsu YC, Hsiao M, Wang LF, Chien YW, Lee WR (2006) Nitric oxide produced by iNOS is associated with collagen synthesis in keloid scar formation. Nitric Oxide 14:327–334CrossRefPubMed
7.
go back to reference Hsu YC, Hsiao M, Chien YW, Lee WR (2007) Exogenous nitric oxide stimulated collagen type I expression and TGF-β1 production in keloid fibroblasts by a cGMP-dependent manner. Nitric Oxide 16:258–265CrossRefPubMed Hsu YC, Hsiao M, Chien YW, Lee WR (2007) Exogenous nitric oxide stimulated collagen type I expression and TGF-β1 production in keloid fibroblasts by a cGMP-dependent manner. Nitric Oxide 16:258–265CrossRefPubMed
8.
go back to reference Hsu YC, Wang LF, Chien YW, Lee WR (2007) Induction of TIMP-1 and HSP47 synthesis in primary keloid fibroblasts by exogenous nitric oxide. J Dermatol Sci 45:37–44CrossRefPubMed Hsu YC, Wang LF, Chien YW, Lee WR (2007) Induction of TIMP-1 and HSP47 synthesis in primary keloid fibroblasts by exogenous nitric oxide. J Dermatol Sci 45:37–44CrossRefPubMed
9.
go back to reference Hsu YC, Weng HC, Lin S, Chien YW (2007) Curcuminoids—cellular uptake by human primary colon cancer cells as quantitated by a sensitive HPLC assay and its relation with the inhibition of proliferation and apoptosis. J Agric Food Chem 55:8213–8222CrossRefPubMed Hsu YC, Weng HC, Lin S, Chien YW (2007) Curcuminoids—cellular uptake by human primary colon cancer cells as quantitated by a sensitive HPLC assay and its relation with the inhibition of proliferation and apoptosis. J Agric Food Chem 55:8213–8222CrossRefPubMed
10.
go back to reference Hu Y, Liang H, Du Y, Zhu Y, Wang X (2010) Curcumin inhibits transforming growth factor-beta activity via inhibition of Smad signaling in HK-2 cells. Am J Nephrol 31:332–341CrossRefPubMed Hu Y, Liang H, Du Y, Zhu Y, Wang X (2010) Curcumin inhibits transforming growth factor-beta activity via inhibition of Smad signaling in HK-2 cells. Am J Nephrol 31:332–341CrossRefPubMed
11.
go back to reference Kwak HJ, Park MJ, Cho H, Park CM, Moon SI, Lee HC, Park IC, Kim MS, Rhee CH, Hong SI (2006) Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res 4:209–220CrossRefPubMed Kwak HJ, Park MJ, Cho H, Park CM, Moon SI, Lee HC, Park IC, Kim MS, Rhee CH, Hong SI (2006) Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res 4:209–220CrossRefPubMed
12.
go back to reference Lin YL, Lin CY, Chi CW, Huang YT (2009) Study on antifibrotic effects of curcumin in rat hepatic stellate cells. Phytother Res 23:927–932CrossRefPubMed Lin YL, Lin CY, Chi CW, Huang YT (2009) Study on antifibrotic effects of curcumin in rat hepatic stellate cells. Phytother Res 23:927–932CrossRefPubMed
13.
go back to reference Lin YT, Wang LF, Hsu YC (2009) Curcuminoids suppress the growth of pharynx and nasopharyngeal carcinoma cells through induced apoptosis. J Agric Food Chem 57:3765–3770CrossRefPubMed Lin YT, Wang LF, Hsu YC (2009) Curcuminoids suppress the growth of pharynx and nasopharyngeal carcinoma cells through induced apoptosis. J Agric Food Chem 57:3765–3770CrossRefPubMed
14.
go back to reference Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, Pentland A, Ryan JL, Ding I (2006) Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines. Int J Radiat Oncol Biol Phys 65:890–898PubMed Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, Pentland A, Ryan JL, Ding I (2006) Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines. Int J Radiat Oncol Biol Phys 65:890–898PubMed
15.
go back to reference Ono K, Naiki H, Yamada M (2006) The development of preventives and therapeutics for Alzheimer’s disease that inhibit the formation of beta-amyloid fibrils (fAbeta), as well as destabilize preformed fAbeta. Curr Pharm Des 12:4357–4375CrossRefPubMed Ono K, Naiki H, Yamada M (2006) The development of preventives and therapeutics for Alzheimer’s disease that inhibit the formation of beta-amyloid fibrils (fAbeta), as well as destabilize preformed fAbeta. Curr Pharm Des 12:4357–4375CrossRefPubMed
16.
go back to reference Panchatcharam M, Miriyala S, Gayathri VS, Suguna L (2006) Curcumin improves wound healing by modulating collagen and decreasing reactive oxygen species. Mol Cell Biochem 290:87–96CrossRefPubMed Panchatcharam M, Miriyala S, Gayathri VS, Suguna L (2006) Curcumin improves wound healing by modulating collagen and decreasing reactive oxygen species. Mol Cell Biochem 290:87–96CrossRefPubMed
17.
go back to reference Perkins S, Verschoyle RD, Hill K, Parveen I, Threadgill MD, Sharma RA, Williams ML, Steward WP, Gescher AJ (2002) Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev 11:535–540PubMed Perkins S, Verschoyle RD, Hill K, Parveen I, Threadgill MD, Sharma RA, Williams ML, Steward WP, Gescher AJ (2002) Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev 11:535–540PubMed
18.
go back to reference Phan TT, Sun L, Bay BH, Chan SY, Lee ST (2003) Dietary compounds inhibit proliferation and contraction of keloid and hypertrophic scar-derived fibroblasts in vitro: therapeutic implication for excessive scarring. J Trauma 54:1212–1224CrossRefPubMed Phan TT, Sun L, Bay BH, Chan SY, Lee ST (2003) Dietary compounds inhibit proliferation and contraction of keloid and hypertrophic scar-derived fibroblasts in vitro: therapeutic implication for excessive scarring. J Trauma 54:1212–1224CrossRefPubMed
19.
go back to reference Pratsinis H, Giannouli CC, Zervolea I, Psarras S, Stathakos D, Kletsas D (2004) Differential proliferative response of fetal and adult human skin fibroblasts to transforming growth factor-beta. Wound Repair Regen 12:374–383CrossRefPubMed Pratsinis H, Giannouli CC, Zervolea I, Psarras S, Stathakos D, Kletsas D (2004) Differential proliferative response of fetal and adult human skin fibroblasts to transforming growth factor-beta. Wound Repair Regen 12:374–383CrossRefPubMed
20.
go back to reference Rahman I, Adcock IM (2006) Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 28:219–242CrossRefPubMed Rahman I, Adcock IM (2006) Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 28:219–242CrossRefPubMed
21.
go back to reference Rodriguez-Melendez R, Zempleni J (2009) Nitric oxide signaling depends on biotin in Jurkat human lymphoma cells. J Nutr 139:429–433CrossRefPubMed Rodriguez-Melendez R, Zempleni J (2009) Nitric oxide signaling depends on biotin in Jurkat human lymphoma cells. J Nutr 139:429–433CrossRefPubMed
22.
go back to reference Ryu EK, Choe YS, Lee KH, Choi Y, Kim BT (2006) Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging. J Med Chem 49:6111–6119CrossRefPubMed Ryu EK, Choe YS, Lee KH, Choi Y, Kim BT (2006) Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging. J Med Chem 49:6111–6119CrossRefPubMed
23.
go back to reference Schäffer MR, Tantry U, Thornton FJ, Barbul A (1999) Inhibition of nitric oxide synthesis in wounds: pharmacology and effect on accumulation of collagen in wounds in mice. Eur J Surg 165:262–267CrossRefPubMed Schäffer MR, Tantry U, Thornton FJ, Barbul A (1999) Inhibition of nitric oxide synthesis in wounds: pharmacology and effect on accumulation of collagen in wounds in mice. Eur J Surg 165:262–267CrossRefPubMed
24.
go back to reference Schäffer MR, Weimer W, Wider S, Stülten C, Bongartz M, Budach W, Becker HD (2002) Differential expression of inflammatory mediators in radiation-impaired wound healing. J Surg Res 107:93–100PubMed Schäffer MR, Weimer W, Wider S, Stülten C, Bongartz M, Budach W, Becker HD (2002) Differential expression of inflammatory mediators in radiation-impaired wound healing. J Surg Res 107:93–100PubMed
25.
26.
go back to reference Sinha R, Anderson DE, McDonald SS, Greenwald P (2003) Cancer risk and diet in India. J Postgrad Med 49:222–228PubMed Sinha R, Anderson DE, McDonald SS, Greenwald P (2003) Cancer risk and diet in India. J Postgrad Med 49:222–228PubMed
27.
go back to reference Tan TW, Tsai HR, Lu HF, Lin HL, Tsou MF, Lin YT, Tsai HY, Chen YF, Chung JG (2006) Curcumin-induced cell cycle arrest and apoptosis in human acute promyelocytic leukemia HL-60 cells via MMP changes and caspase-3 activation. Anticancer Res 26:4361–4371PubMed Tan TW, Tsai HR, Lu HF, Lin HL, Tsou MF, Lin YT, Tsai HY, Chen YF, Chung JG (2006) Curcumin-induced cell cycle arrest and apoptosis in human acute promyelocytic leukemia HL-60 cells via MMP changes and caspase-3 activation. Anticancer Res 26:4361–4371PubMed
28.
go back to reference Thomas DW, Hopkinson I, Harding KG, Shepherd JP (1994) The pathogenesis of hypertrophic/keloid scarring. Int J Oral Maxillofac Surg 23:232–236CrossRefPubMed Thomas DW, Hopkinson I, Harding KG, Shepherd JP (1994) The pathogenesis of hypertrophic/keloid scarring. Int J Oral Maxillofac Surg 23:232–236CrossRefPubMed
29.
go back to reference Wang XQ, Liu YK, Qing C, Lu SL (2009) A review of the effectiveness of antimitotic drug injections for hypertrophic scars and keloids. Ann Plast Surg 63:688–692CrossRefPubMed Wang XQ, Liu YK, Qing C, Lu SL (2009) A review of the effectiveness of antimitotic drug injections for hypertrophic scars and keloids. Ann Plast Surg 63:688–692CrossRefPubMed
30.
go back to reference Yamamoto T, Eckes B, Krieg T (2000) Bleomycin increases steady-state levels of type I collagen, fibronectin and decorin mRNAs in human skin fibroblasts. Arch Dermatol Res 292(11):556–561CrossRefPubMed Yamamoto T, Eckes B, Krieg T (2000) Bleomycin increases steady-state levels of type I collagen, fibronectin and decorin mRNAs in human skin fibroblasts. Arch Dermatol Res 292(11):556–561CrossRefPubMed
31.
go back to reference Zhang L, Keane MP, Zhu LX, Sharma S, Rozengurt E, Strieter RM, Dubinett SM, Huang M (2004) Interleukin-7 and transforming growth factor-beta play counter-regulatory roles in protein kinase C-delta-dependent control of fibroblast collagen synthesis in pulmonary fibrosis. J Biol Chem 279:28315–28319CrossRefPubMed Zhang L, Keane MP, Zhu LX, Sharma S, Rozengurt E, Strieter RM, Dubinett SM, Huang M (2004) Interleukin-7 and transforming growth factor-beta play counter-regulatory roles in protein kinase C-delta-dependent control of fibroblast collagen synthesis in pulmonary fibrosis. J Biol Chem 279:28315–28319CrossRefPubMed
Metadata
Title
Suppression of TGF-β1/SMAD pathway and extracellular matrix production in primary keloid fibroblasts by curcuminoids: its potential therapeutic use in the chemoprevention of keloid
Authors
Yi-Chiang Hsu
Ming-Jenn Chen
Ya-Mei Yu
Shun-Yao Ko
Chi-Chang Chang
Publication date
01-12-2010
Publisher
Springer-Verlag
Published in
Archives of Dermatological Research / Issue 10/2010
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI
https://doi.org/10.1007/s00403-010-1075-y

Other articles of this Issue 10/2010

Archives of Dermatological Research 10/2010 Go to the issue