Skip to main content Skip to main navigation menu Skip to site footer

Effect of pirfenidone and its combination with 5-fluorouracil on keloid fibroblast proliferation and collagen deposition: in vitro study

  • Nugrohoaji Dharmawan ,
  • Agung Triana Hartati ,
  • Indah Julianto ,
  • Harijono Kariosentono ,


Abstract

Background: Keloid is a fibroproliferative disease in which its etiology remains unknown. Various therapy modalities have been improved, but none of them gives a satisfying outcome. Pirfenidone (PFD) is a commonly used drug in pulmonary fibrotic diseases, which has an anti-fibrotic effect. 5-fluorouracil (5-FU) is one of the keloid therapy choices that has long been used. This study aimed to investigate PFD's effect and its combination with 5-FU on fibroblast proliferation and collagen deposition.

Methods: This experimental study using post only control group design was conducted by comparing PFD in various doses (0.5, 1.0, 1.5, 2.0, 3.0 mg/ml) and its combination with 5-FU on keloid fibroblast proliferation and collagen deposition. We used MTT (3-[4,5-dimethylthiazol-2-yl}-2,5diphenyl tetrazolium bromide) and Sirius Red assays to measure the fibroblast proliferation and collagen deposition, respectively. The statistical analysis used one-way ANOVA with p-value p<0.05 was considered significant.

Results: The combination of PFD 3.0 mg/ml + 5-FU 1.0 mg/ml had more significant effect on inhibiting fibroblast proliferation as well as decreasing collagen deposition compared to 5-FU only (p<0.043). PFD 1.0 mg/ml + 5-FU 1 mg/ml as well as PFD 1.5 mg/ml+ 5-FU 1 mg/ml are more effective in inhibiting fibroblast proliferation and lowering collagen deposition than PFD only with p values of <0.001 and <0.000, respectively.

Conclusion: In general, PFD, as well as 5-FU, are effective in inhibiting fibroblast proliferation and decreasing collagen deposition in keloid. However, the combination of both has a better effect compared to PFD or 5-FU monotherapy.
Keywords: 5-Fluorouracil collagen deposition keloid fibroblast pirfenidone proliferation

References

  1. Mari W, Alsabri SG, Tabal N, Younes S, Sherif A & Simman R. Novel Insights on Understanding of Keloid Scar: Article Review. J Am Coll Clin Wound Spec. 2015;7(1-3): 1-7.
  2. Shaheen A. Comprehensive Review of Keloid Formation. Clin Res Dermatol Open Access. 2017;4(5): 1-18
  3. Halim AS, Emami A, Salahshourifar I, Kannan TP. Keloid scarring: understanding the genetic basis, advances, and prospects. Arch Plast Surg. 2012;39(3):184-9.
  4. Glass DA. Current Understanding of the Genetic Causes of Keloid Formation. J Investig Dermatol Symp Proc. 2017;18(2): S50-S53.
  5. Butler PD, Longaker MT, Yang GP. Current progress in Keloid Research and Treatment. J Am Coll Surg. 2008;206(4):731-41.
  6. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17(1-2):113-25.
  7. Bijlard E, Steltenpool S, Niessen FB. Intralesional 5-fluorouracil in keloid treatment: a systematic review. Acta Derm Venereol. 2015;95(7):778-82.
  8. Hall CL, Wells AR, Leung KP. Pirfenidone reduces profibrotic responses in human dermal myofibroblasts in vitro. Lab Invest. 2018;98(5): 640-655.
  9. Shi K, Wang F, Xia J, Zuo B, Wang Z, Cao X. Pirfenidone Inhibits Epidural Scar Fibroblast Proliferation and Differentiation by Regulating TGF-β1-Induced Smad-dependent and -independent Pathways. Am J Transl Res. 2019;11(3): 1593-1604.
  10. Taskiran D, Taskiran E, Yercan H, Kutay FZ. Quantification of Total Collagen in Rabbit Tendon by the Sirius Red Method. Tr. J. of Medical Sciences. 1999;(29) 7-9.
  11. Wirohadidjojo YW, Budiyanto A, Soebono H. Regenerative Effects of Wharton's Jelly Stem Cells-Conditioned Medium in UVA-Irradiated Human Dermal Fibroblasts. Malays. J Med Biol. Res. 2016;3(1):45-50.
  12. Ghazawi FM, Zargham R, Mirko SG, Sasseville D, Jafarian F. Insights into the Pathophysiology of Hypertrophic Scars and Keloids: How Do They Differ? Adv. Skin Wound Care. 2018;31(1):581-594.
  13. Xue M, Jackson CJ. Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring. Adv Wound Care (New Rochelle). 2015;4(3):119-136.
  14. Taheri A, Habibi I, Hedayatyanfard K, Farazmand F, Habibi B. Botulinum toxin type A (BTX-A) to improve the treatment of keloid and hypertrophic scars: A double-blinded randomized clinical trial. Bali Med J. 2019;8(1):30-34
  15. Focaccetti C et al. Effects of 5-Fluorouracil on Morphology, Cell Cycle, Proliferation, Apoptosis, Autophagy and ROS Production in Endothelial Cells and Cardiomyocytes. PLoS One. 2015
  16. Muhale FA, Wetmore BA, Thomas RS, McLeod HL. Systems pharmacology assessment of the 5-fluorouracil pathway. Pharmacogenics. 2011;12(3):341-350.
  17. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-8.
  18. Huang L, Wong YP, Cai YJ, Lung I, Leung CS, Burd A. Low-dose 5-fluorouracil induces cell cycle G2 arrest and apoptosis in keloid fibroblasts. Br J Dermatol. 2010;163(6):1181-5.
  19. Ibrahim A, Chalhoub RS. 5-FU for problematic Scarring: A Review of The Literature. Ann Burns Fire Disasters. 2018;31(2):133-137.
  20. Barragan JM, Rodriguez AS, Partida J, Borunda JA. The Multifaceted Role of Pirfenidone and Its Novel Targets. Fibrogenesis and Tissue Repair. 2010;3(16):1-11.
  21. Kadir SI, Wenzel KT, Dige A, Kok Jensen S, Dahlerup JF, Kelsen J. Pirfenidone inhibits the proliferation of fibroblasts from patients with active Crohn's disease. Scand J Gastroenterol. 2016;51(11):1321-5.
  22. Lin X, Yuan H, Zhong H. Effects of Pirfenidone on Proliferation, Migration, and Collagen Contraction of Human Tenon's Fibroblasts In Vitro. Investi Ophthalmol Vis Sci. 2009; 50(8):3762-3770.
  23. Lee K, Young Lee S, Park SY, Yang H. Antifibrotic effect of pirfenidone on human pterygium fibroblasts. Curr Eye Res. 2014;39(7):680-5.
  24. Sun Y, Zhang Y, Chi P. Pirfenidone suppresses TGFbeta1induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway. Mol Med Rep. 2018;18(4):3907-3913.
  25. Zou WJ, Huang Z, Jiang TP, Shen YP, Zhao AS, Zhou S, Zhang S. Pirfenidone Inhibits Proliferation and Promotes Apoptosis of Hepatocellular Carcinoma Cells by Inhibiting the Wnt/beta-Catenin Signaling Pathway. Med Sci Monit. 2017;236107-6113.
  26. Huang L, Cai YJ, Lung I, Leung BC, Burd AA. Study of the combination of triamcinolone and 5-fluorouracil in modulating keloid fibroblasts in vitro. J Plast Reconstr Aesthet Surg. 2013;66(9):e251-9.

How to Cite

Dharmawan, N., Hartati, A. T., Julianto, I., & Kariosentono, H. (2020). Effect of pirfenidone and its combination with 5-fluorouracil on keloid fibroblast proliferation and collagen deposition: in vitro study. Bali Medical Journal, 9(2), 496–500. https://doi.org/10.15562/bmj.v9i2.1778
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver
Download Citation
Endnote/Zotero/Mendeley (RIS) BibTeX

HTML
1

Total
16

Share

Search Panel

Nugrohoaji Dharmawan
Google Scholar
Pubmed
BMJ Journal

Agung Triana Hartati
Google Scholar
Pubmed
BMJ Journal

Indah Julianto
Google Scholar
Pubmed
BMJ Journal

Harijono Kariosentono
Google Scholar
Pubmed
BMJ Journal