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Dietary Compounds Inhibit Proliferation and Contraction of Keloid and Hypertrophic Scar-Derived Fibroblasts In Vitro: Therapeutic Implication for Excessive Scarring

Phan, Toan-Thang MD; Sun, Li MD; Bay, Boon-Huat PhD; Chan, Sui-Yung PhD; Lee, Seng-Teik FRCS, FAMS

The Journal of Trauma: Injury, Infection, and Critical Care: June 2003 - Volume 54 - Issue 6 - p 1212–1224
doi: 10.1097/01.TA.0000030630.72836.32
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Background: Keloid and hypertrophic scars commonly occur after injuries. Overproliferation of fibroblasts, overproduction of collagen, and contraction characterize these pathologic scars. Current treatment of excessive scars with intralesional corticosteroid injections used individually or in combination with other methods often have unsatisfactory outcome, frustrating both the patient and the clinician. The phytochemical compounds are well known as potential anticancer agents. We have investigated the inhibitory effects of compounds on keloid fibroblasts (KF) and hypertrophic scar-derived fibroblasts (HSF).

Methods: Fibroblasts were cultured from nontreated earlobe keloids and burn hypertrophic scars. Ten compounds (three hydroxybenzoic and four hydroxycinnamic acid derivatives, two flavonols [quercetin and kaempferol], and turmeric curcumin) were tested with fibroblasts. The inhibitory effects of compounds on fibroblasts was assessed by proliferation assays, fibroblast-populated collagen lattice (FPCL) contraction, and electron microscopy.

Results: The phytochemicals significantly inhibited KF and HSF proliferation in a dose- and time-dependent manner. In the hydroxybenzoic and flavonol groups, increasing inhibitory effects seemed to depend on increasing numbers of hydroxyl groups in their chemical structures. This phenomenon was not observed in the hydroxycinnamic acid group. The phytochemicals inhibited fibroblast proliferation by inducing cell growth arrest but not apoptosis. The reversibility of growth inhibition occurred when the compounds were removed from the culture and fresh media was replaced. Slower reversibility of growth inhibition was observed in the groups treated with quercetin, chlorogenic acid, or curcumin. The compounds quercetin, gallic acid, protocatechuic acid, and chlorogenic acid were the strongest inhibitors of FPLC contraction by HTFs. When the compounds were washed out of the lattices and replaced by fresh medium, the FPCL contraction was resumed. The resumption of FPCL contraction was slowest in the quercetin-treated group, indicating again the strong inhibitory effect of quercetin.

Conclusion: From this in vitro study, quercetin seemed to have good potent effects to inhibit proliferation and contraction of excessive scar-derived fibroblasts.

From the Departments of Plastic Surgery (T.-T.P., S.-T.L.) and Clinical Research (L.S.), Singapore General Hospital, and Departments of Anatomy (B.-H.B.) and Pharmacy (S.-Y.C.), National University of Singapore, Republic of Singapore.

Submitted for publication December 31, 2001.

Accepted for publication July 3, 2002.

Supported by grants from the National Medical Research Council of Singapore (NMRC/0204/1997), Department of Clinical Research, Singapore General Hospital, and SingHealth Research Grant (EX021/2001).

Address for reprints: Toan-Thang Phan, MD, Department of Surgery/Division of Bioengineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260; email: surptt@nus.edu.sg.

© 2003 Lippincott Williams & Wilkins, Inc.