Topical Treatment of Hair Loss with Formononetin by Modulating Apoptosis

Mi Hye Kim; You Yeon Choi; Ji Eun Lee; Kyuseok Kim; Woong Mo Yang

doi:10.1055/s-0035-1557897

Planta Medica, Table of Contents

Planta Med 2016; 82(01/02): 65-69
DOI: 10.1055/s-0035-1557897

Biological and Pharmacological Activitiy

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Topical Treatment of Hair Loss with Formononetin by Modulating Apoptosis

Mi Hye Kim

¹College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, Seoul, Korea

,

You Yeon Choi

¹College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, Seoul, Korea

,

Ji Eun Lee

¹College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, Seoul, Korea

,

Kyuseok Kim

²Department of Ophthalmology, Otorhinolaryngology and Dermatology of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea

,

Woong Mo Yang

¹College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, Seoul, Korea

› Author Affiliations

Abstract

Formononetin is one of the main components of red clover plants and its role on hair regrowth against hair loss has not been established yet. In the present study, we assessed the potential effects of formononetin on alopecia, along with impaired hair cycles by induction of apoptosis-regression.

Depilated C57BL/6 mice were used for monitoring the hair cycles. Formononetin (1 and 100 µM) was topically treated to the dorsal skin for 14 days. Topical formononetin treatment induced miniaturized hair follicles to recover to normal sizes. Tapering hair shaft began to grow newly, emerging from the hair follicles by formononetin. In addition, formononetin inhibited the activation of caspase-8 and decreased the procaspase-9 expression. As a result of formononetin treatment, anti-apoptotic Bcl-2 was up-regulated, whereas pro-apoptotic Bax and p53 were down-regulated, resulting in a decrease of caspase-3 activation. Formononetin showed the obvious inhibition of apoptosis under terminal deoxynucleotidyl transferase dUTP nick end labeling staining thereafter.

Taken together, our findings demonstrate that formononetin exerted the hair regrowth effect on hair loss, in which the underlying mechanisms were associated with Fas/Fas L-induced caspase activation, thus inhibiting apoptosis.

Key words

formononetin - hair loss - hair cycle - apoptosis - caspase

Full Text

References

References
1 Botchkareva NV, Ahluwalia G, Shander D. Apoptosis in the hair follicle. J Invest Dermatol 2006; 126: 258-264
2 Gafter-Gvili A, Sredni B, Gal R, Gafter U, Kalechman Y. Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes. Am J Physiol Cell Physiol 2003; 284: C1593-C1603
3 Peters EM, Foitzik K, Paus R, Ray S, Holick MF. A new strategy for modulating chemotherapy-induced alopecia, using PTH/PTHrP receptor agonist and antagonist. J Invest Dermatol 2001; 117: 173-178
4 Gregoriou S, Papafragkaki D, Kontochristopoulos G, Rallis E, Kalogeromitros D, Rigopoulos D. Cytokines and other mediators in alopecia areata. Mediators Inflamm 2010; 2010: 928030
5 Park HJ, Zhang N, Park DK. Topical application of Polygonum multiflorum extract induces hair growth of resting hair follicles through upregulating Shh and beta-catenin expression in C57BL/6 mice. J Ethnopharmacol 2011; 135: 369-375
6 Chandrashekar BS, Nandhini T, Vasanth V, Sriram R, Navale S. Topical minoxidil fortified with finasteride: An account of maintenance of hair density after replacing oral finasteride. Indian Dermatol Online J 2015; 6: 17-20
7 Glina S, Neves PA, Saade R, Netto Jr NR, Soares JB, Galuppo AG. Finasteride-associated male infertility. Rev Hosp Clin Fac Med Sao Paulo 2004; 59: 203-205
8 Boersma IH, Oranje AP, Grimalt R, Iorizzo M, Piraccini BM, Verdonschot EH. The effectiveness of finasteride and dutasteride used for 3 years in women with androgenetic alopecia. Indian J Dermatol Venereol Leprol 2014; 80: 521-525
9 DeVillez RL. The therapeutic use of topical minoxidil. Dermatol Clin 1990; 8: 367-375
10 Mu H, Bai YH, Wang ST, Zhu ZM, Zhang YW. Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine 2009; 16: 314-319
11 Lipovac M, Chedraui P, Gruenhut C, Gocan A, Kurz C, Neuber B, Imhof M. Effect of red clover isoflavones over skin, appendages, and mucosal status in postmenopausal women. Obstet Gynecol Int 2011; 2011: 949302
12 Auyeung KK, Ko JK. Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell. Invest New Drugs 2010; 28: 1-13
13 Lo YL, Wang W. Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chem Biol Interact 2013; 205: 188-197
14 Virk-Baker MK, Nagy TR, Barnes S. Role of phytoestrogens in cancer therapy. Planta Med 2010; 76: 1132-1142
15 Ye Y, Hou R, Chen J, Mo L, Zhang J, Huang Y, Mo Z. Formononetin-induced apoptosis of human prostate cancer cells through ERK1/2 mitogen-activated protein kinase inactivation. Horm Metab Res 2012; 44: 263-267
16 Jin YM, Xu TM, Zhao YH, Wang YC, Cui MH. In vitro and in vivo anti-cancer activity of formononetin on human cervical cancer cell line HeLa. Tumour Biol 2014; 35: 2279-2284
17 Chen J, Zhao X, Ye Y, Wang Y, Tian J. Estrogen receptor beta-mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and formononetin. Cell Physiol Biochem 2013; 32: 1790-1797
18 Muller-Rover S, Rossiter H, Paus R, Handjiski B, Peters EM, Murphy JE, Mecklenburg L, Kupper TS. Overexpression of Bcl-2 protects from ultraviolet B-induced apoptosis but promotes hair follicle regression and chemotherapy-induced alopecia. Am J Pathol 2000; 156: 1395-1405
19 Saggioro FP, Neder L, Stavale JN, Paixao-Becker AN, Malheiros SM, Soares FA, Pittella JE, Matias CC, Colli BO, Carlotti Jr CG, Franco M. Fas, FasL, and cleaved caspases 8 and 3 in glioblastomas: a tissue microarray-based study. Pathol Res Pract 2014; 210: 267-273
20 Hellwig CT, Passante E, Rehm M. The molecular machinery regulating apoptosis signal transduction and its implication in human physiology and pathophysiologies. Curr Mol Med 2011; 11: 31-47
21 Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 2003; 10: 26-35
22 Schultz DR, Harrington jr. WJ. Apoptosis: programmed cell death at a molecular level. Semin Arthritis Rheum 2003; 32: 345-369
23 De Martino L, Marfe G, Longo M, Fiorito F, Montagnaro S, Iovane V, Decaro N, Pagnini U. Bid cleavage, cytochrome c release and caspase activation in canine coronavirus-induced apoptosis. Vet Microbiol 2010; 141: 36-45
24 Hu Q, Cui X, Tao L, Xiu L, Wang T, Wang X. Staphylococcus aureus induces apoptosis in primary bovine mammary epithelial cells through Fas-FADD death receptor-linked caspase-8 signaling. DNA Cell Biol 2014; 33: 388-397
25 van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P. Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun 2003; 304: 487-497
26 Huang GJ, Pan CH, Liu FC, Wu TS, Wu CH. Anti-inflammatory effects of ethanolic extract of Antrodia salmonea in the lipopolysaccharide-stimulated RAW246.7 macrophages and the lambda-carrageenan-induced paw edema model. Food Chem Toxicol 2012; 50: 1485-1493
27 Lindner G, Botchkarev VA, Botchkareva NV, Ling G, van der Veen C, Paus R. Analysis of apoptosis during hair follicle regression (catagen). Am J Pathol 1997; 151: 1601-1617
28 Sharov AA, Li GZ, Palkina TN, Sharova TY, Gilchrest BA, Botchkarev VA. Fas and c-kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss. J Invest Dermatol 2003; 120: 27-35
29 Botchkarev VA, Komarova EA, Siebenhaar F, Botchkareva NV, Komarov PG, Maurer M, Gilchrest BA, Gudkov AV. p 53 is essential for chemotherapy-induced hair loss. Cancer Res 2000; 60: 5002-5006
30 Kim MH, Kim SH, Yang WM. Beneficial effects of astragaloside IV for hair loss via inhibition of Fas/Fas L-mediated apoptotic signaling. PLoS One 2014; 9: e92984
31 Kim MH, Choi YY, Cho IH, Hong J, Kim SH, Yang WM. Angelica sinensis induces hair regrowth via the inhibition of apoptosis signaling. Am J Chin Med 2014; 42: 1021-1034