Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia

BMC Clinical Pharmacology

Jerry Pelletier³  Scott W Lowe⁷  John A Porco Jr⁵  Pierre Deslongchamps⁴  Ragam Somaiah⁴  Kontham Ravindar⁴  Jennifer Chu¹  Marilene Paquet⁶  Lukas E Dow²  Zeina Nasr¹ 

[1] Departments of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada;Memorial Sloan-Kettering Cancer Center, New York, USA;The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6, Canada;Départment de Chimie, Université Laval, Ste-Foy, Quebec G1V 0A6, Canada;Center for Methodology and Library Development, Boston University, 590 Commonwealth Ave., Boston, MA 02215, USA;Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec J2S 2 M2, Canada;Howard Hughes Medical Institute, New York, NY 10065, USA

关键词: Cyclophosphamide;    Genetic engineered mouse model;    Translation initiation;    eIF4A;    eIF4E;    Chemotherapy-induced alopecia;   

Others  :  860488
DOI  :  10.1186/2050-6511-14-58

 received in 2013-08-28, accepted in 2013-11-08,  发布年份 2013

【 摘 要 】

Background

Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings.

Methods

The eukaryotic initiation factor (eIF) 4E is a cap binding protein that stimulates ribosome recruitment to mRNA templates during the initiation phase of translation. Suppression of eIF4E is known to induce cell cycle arrest. Using a novel inducible and reversible transgenic mouse model that enables RNA_i-mediated suppression of eIF4E in vivo, we assessed the consequences of temporal eIF4E suppression on CIA.

Results

Our results demonstrate that transient inhibition of eIF4E protects against cyclophosphamide-induced alopecia at the organismal level. At the cellular level, this protection is associated with an accumulation of cells in G1, reduced apoptotic indices, and was phenocopied using small molecule inhibitors targeting the process of translation initiation.

Conclusions

Our data provide a rationale for exploring suppression of translation initiation as an approach to prevent or minimize cyclophosphamide-induced alopecia.

【 授权许可】

   
2013 Nasr et al.; licensee BioMed Central Ltd.

【 图 表 】

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