010 Molecular control of chemotherapy-induced hair loss: essential roles for p53 and its target genes

V.A. Botchkarev1, E.A. Komarova2, F. Siebenhaar1,3, N.V. Botchkareva1, P.G. Komarov2, M. Maurer3, A.V. Gudkov2, and B.A. Gilchrest1. Dept. of Dermatology, Boston University School of Medicine 1, Dept of Molecular Genetics, University of Illinois at Chicago 2, Dept. of Dermatology, University of Mainz, Germany 3.

Anticancer drugs induce apoptosis in the hair follicles and hair loss, the most common side effect of chemotherapy. In C57BL/6 mouse model for chemotherapy-induced hair loss, we demonstrate that p53 is essential for this process: (i) by immunohistology, p53 was upregulated in the hair follicles after cyclophosphamide treatment, (ii) in contrast to wild type mice, p53-deficient mice show neither hair loss nor apoptosis in the hair follicle keratinocytes that maintained active proliferation after cyclophosphamide treatment, (iii) hair follicles in p53 knockout mice are characterized by downregulation of Fas and insulinlike growth factor binding protein-3, and increased expression of Bcl-2. To confirm a role for Fas as a p53 target gene in chemotherapy-induced hair loss, we show that Fas knockout mice display significant (p<0.05) retardation of cyclophosphamide-induced hair follicle regression and decrease of intrafollicular apoptosis. Furthermore, administration of Fas-ligand neutralizing antibody significantly reduced a number of apoptotic cells in the hair follicle and retarded a rate of hair follicle involution induced by cyclophosphamide. These observations indicate that local pharmacological inhibition of p53 and/or its target genes may be useful to prevent chemotherapy-associated hair loss.