Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia
Dow, Lukas E.
Porco, John A.
Lowe, Scott W.
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Citation (published version)Zeina Nasr, Lukas E Dow, Marilene Paquet, Jennifer Chu, Kontham Ravindar, Ragam Somaiah, Pierre Deslongchamps, John A Porco, Scott W Lowe, Jerry Pelletier. 2013. "Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia.." BMC Pharmacol Toxicol, Volume 14, pp. 58.
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 RNAi-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.