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1 Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: ljohn{at}physio1.utmem.edu.
We previously have shown that polyamine depletion delays apoptosis in rat
intestinal epithelial (IEC-6) cells (Am J Physiol Cell Physiol. 278: C480-489, 2000).
Here we demonstrate that polyamine depletion inhibits 
-irradiation induced apoptosis in
vitro and in vivo. Pretreatment of IEC-6 cells with 5 mM 
-difluoromethylornithine
(DFMO) for 4 days significantly reduced radiation-induced caspase-3 activity and DNA
fragmentation. This protective effect was prevented by the addition of 10 µM exogenous
putrescine. Radiation exposure to mice resulted in a high frequency of apoptosis over
cells positioned 4th to 7th in crypt-villus units. Pretreatment of mice with 2% DFMO in
drinking water significantly reduced apoptotic cells from approximately 2.75 to 1.61 per
crypt-villus unit, accompanied by significant decreases in caspase-3 levels. Further
examination showed that DFMO pretreatment inhibited the radiation-induced increase in
the pro-apoptotic protein Bax. Moreover, DFMO pretreatment significantly enhanced the
intestinal crypt survival rate by 2.1 fold subsequent to radiation and ameliorated mucosal
structural damage. We conclude that polyamine depletion by DFMO inhibits -irradiation
induced apoptosis of intestinal epithelia cells both in vitro & in vivo through inhibition of
Bax and caspase-3 activity, which leads to attenuation of radiation inflicted intestinal
injury. These data indicate that DFMO may be therapeutically useful to counteract the
gastrointestinal toxicity caused by chemo-radiotherapy. This is the first demonstration
that polyamines are required for apoptosis in vivo.
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