Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia.
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.
Zeina
Z
Nasr
Lukas E
LE
Dow
Marilene
M
Paquet
Jennifer
J
Chu
Kontham
K
Ravindar
Ragam
R
Somaiah
Pierre
P
Deslongchamps
John A
JA
Porco
Scott W
SW
Lowe
Departments of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada. jerry.pelletier@mcgill.ca.
Jerry
J
Pelletier
D000505:Alopecia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D004318:Doxycycline / Q000008:administration & dosage / Q000009:adverse effects*; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics
D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D034741:RNA, Small Interfering; D003520:Cyclophosphamide; D004318:Doxycycline