Halofuginone mediated protection against radiation-induced leg contracture.
Fibrosis of normal tissues often accompanies radiation treatment of cancer. Activation of the transforming growth factor-beta (TGF-beta) signaling pathway is thought to play a major role in radiation-induced fibrosis and has prompted the development and assessment of low molecular weight inhibitors of the pathway. Previous studies with halofuginone have shown it to inhibit TGF-beta signaling in vitro and protect mice from radiation-induced leg contraction (a model for soft tissue fibrosis). The current study confirms these findings for HaCaT cells stimulated with exogenous TGF-beta treatment. Reducing the halifuginone treatment from 7 days/week (used previously) to 5 days/week post-radiation exposure provided significant protection against radiation-induced leg contraction in mice 3 and 4 months post-radiation treatment. Halofuginone treatment was shown to attenuate TGF-beta signaling molecules taken from irradiated skin including TGF-betaRII, pSmad3, Smad7, and TSP1. The latter, TSP1, a co-activator of TGF-beta may serve as a suitable biomarker for monitoring the efficacy of halofuginone should it be evaluated in a clinical setting for protection against radiation-induced fibrosis.
Ishii
Hisanari
H
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1002, USA.
Choudhuri
Rajani
R
Mathias
Askale
A
Sowers
Anastasia L
AL
Flanders
Kathleen C
KC
Cook
John A
JA
Mitchell
James B
JB
D000818:Animals; D002460:Cell Line; D003286:Contracture / Q000517:prevention & control*; D005260:Female; D005355:Fibrosis / Q000517:prevention & control*; D006801:Humans; D007866:Leg; D051379:Mice; D008809:Mice, Inbred C3H; D010880:Piperidines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D052999:Quinazolinones / Q000494:pharmacology*; D011878:Radiotherapy / Q000009:adverse effects*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D010880:Piperidines; D052999:Quinazolinones; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C010176:halofuginone