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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online December 4, 2003 as doi:10.1096/fj.03-0552fje. |
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C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, 52900 Israel;
* Departments of Pathology and Nephrology, Rabin Medical Center-Golda Campus, Petah Tikva, 49372 Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
Institute of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel, Rabin Medical Center Petah Tikva, 49372 Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel; and
Department of Biochemistry, Cornell University Medical College, New York, New York 10021, USA
2 Corespondence: C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, 52900 Israel. E-mail: srednib{at}mail.biu.ac.il
SPECIFIC AIMS
The synthetic nontoxic Tellurium compound AS101, currently used in clinical trials on cancer patients, has been found to protect cancer patients from chemotherapy-induced bone marrow toxicity and alopecia. The aim of the present study was to evaluate the ability of AS101 to induce hair growth and to gain insight into the mechanism of action of this effect.
PRINCIPAL FINDINGS
1. Induction of hair growth by AS101 in mice
The ability of AS101 to induce hair growth was studied in several mouse models. In nude mice AS101 induced a pronounced dose-dependent increase in hair growth when administered either systematically (i.p.), orally, or topically (Fig. 1
). It appears that exogenously administered AS101 stimulates hair growth in nu/nu athymic mice by stimulating follicular proliferation (increase in BrdU-labeled follicular keratinocytes) and inducing normalization of the nu/nu follicular keratin differentiation defect (relatively normal follicles containing well-differentiated straight hair shafts showing clear birefringence of the cuticle). AS101 also accelerates, in a dose-dependent manner, hair regrowth in Balb/c mice whose dorsal hair is depilated.
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2. Hair cycle modulation by AS101
The ability of AS101 to induce hair growth in nude mice and to accelerate hair regrowth in normal mice led us to evaluate the modulation of hair cycle by the compound. Using the C57BL/6 mouse model for hair research by assessing defined, hair cycle-dependent cutaneous color changes, we found that AS101 possesses the dual ability to induce anagen and to retard spontaneous catagen development (Fig. 2
). On day 11 after induction of anagen by depilation, 73.3% of AS101-treated mice displayed anagen vs. only 13.3% in PBS injected control mice. Induction of anagen was prominent at all days tested and was AS101 dose dependent. With regard to catagen induction, 83.3% of all PBS-treated control mice had spontaneously reentered telogen via catagen at day 18 vs. 13.3% of mice treated with AS101. Retardation of catagen was significant at all doses of AS101 and was dose dependent.
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3. KGF mediates AS101-induced hair growth
The mechanism of anagen induction by AS101 was explored in nude and normal mice. Induction of anagen is exerted by AS101 by promotion of follicular keratinocyte proliferation through up-regulation of KGF expression via a unique activation of the ras signaling pathway. It interacts with the most exposed cysteine residue (cys118)on the ras molecule, activates ras, raf, erk1/erk2 resulting in the up-regulation of fibroblast KGF. Each of these steps is mandatory for the up-regulation of KGF expression by AS101, which is essential for hair growth induction by the compound. Neutralization of KGF in nude mice treated with AS101 abolished hair growth-inducing capabilities of the compound. Moreover, the role of KGF in AS101’s ability to induce hair growth was also assessed in transgenic mice. For this purpose we used homozygous and heterozygous transgenic mice of SJL/B6 origin expressing a negative KGF receptor transgene in basal keratinocytes. AS101 treatment did not stimulate hair growth of homozygous transgenic mice at any concentration, whereas it considerably affected the pattern of hair growth of normal mice in a dose-dependent manner; nevertheless some activity of AS101 was observed in heterozygous transgenic mice implying a strong correlation between transgene expression and the ability of AS101 to induce hair growth, suggesting an important role of KGF in AS101-induced hair growth.
4. AS101 retards catagen by delaying follicular keratinocyte terminal differentiation
Retardation of catagen by AS101 was exerted via interference with the terminal differentiation process in follicular keratinocytes by an exclusive mechanism of action: up-regulation of p21waf for relatively sustained periods of time, thus excluding the ability of the cells to undergo terminal differentiation (characteristic to follicular keratinocytes in catagen), a process that requires the disappearance of this CDK inhibitor expression. This unique mechanism of AS101 activity could be demonstrated both in vivo (nude and depilated C57BL/6 mice) and in vitro (follicular keratinocytes induced to differentiate by high calcium concentrations), and could not be obtained in follicular keratinocytes from p21waf null mice.
5. AS101 up-regulates KGF expression in human dermal fibroblasts and delays human follicular keratinocyte terminal differentiation in vitro
The above mentioned results obtained in mice cells prompted us to evaluate whether the main relevant abilities of AS101 can be reproduced in human cells. We show similar in vitro findings regarding retardation of terminal differentiation of keratinocytes, in human normal primary keratinocyte cultures or transformed HaCaT keratinocytes cultures, and those regarding KGF production, in normal human fibroblasts. Similarly to the results obtained in mouse fibroblasts, p21ras and its downstream effector molecules c-raf-1 and the MAPK erk1/erk2 were obligatory for the up-regulation of human KGF expression and secretion by AS101 since their inhibition abrogated AS101’s effect. Moreover, AS101-induced delayed expression of terminally differentiation markers in human keratinocytes was associated with sustained elevation of p21waf.
6. Induction of hair growth in humans
Based on the results presented herein, pilot case report studies have been initiated to evaluate hair growth potential of AS101 in humans. The compound was topically applied on 3 adolescents who had remained partially alopeciac long after termination of chemotherapy. Treatment with AS101 resulted in Grade I hair growth in the female R.L. The male O.D exhibited grade II hair growth while grade III was seen in the female C.T. No regression in hair growth was found in the adolescents during the overall 3 months treatment period. They reported no side effects and expressed satisfaction with hair growth. These encouraging results form the basis of a more extensive study.
CONCLUSIONS AND SIGNIFICANCE
We report here on the potentially therapeutic effects of AS101, an immunomodulator currently used in clinical trials. The novelty of the study emanates from AS101’s unique mechanism of action at the cellular and molecular level and the new approach presented here, which may lead to a reconceptualization of the treatment of different types of alopecia. Tellurium compounds are introduced for the first time as agents able to induce hair growth by systemic, oral, or topical administration in normal and nude mice and in pilot human studies.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0552fje 
This article has been cited by other articles:
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  B. Sredni, R. Geffen-Aricha, W. Duan, M. Albeck, F. Shalit, H. M. Lander, N. Kinor, O. Sagi, A. Albeck, S. Yosef, et al. Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson's disease models FASEB J, June 1, 2007; 21(8): 1870 - 1883. [Abstract] [Full Text] [PDF]
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