Page 377 - 2014 Printable Abstract Book
P. 377
paralleled with the enhanced mitochondrial ATP generation, and 53BP1 but not Rad51 was detected in
the foci assay indicating that non-homologous end joining (NHEJ) pathway is involved for the
radioadaptive response in MCF-10A cells. These data suggest that nuclear DNA repair ability is conjugated
with enhanced mitochondrial bioenergetics regulated by mitochondria localized Cyclin B1/CDK1.
(PS7-42) Inhibition of TGF-β activation by small molecular IPW-5371 may protect against radiation-
1
1
1
1
induced intestinal and hematopoietic injury. Lijian Shao ; Rupak Pathak ; Wei Feng ; Jianhui Chang ;
1;3
1
1
1
2
Junru Wang ; Marjan Boerma ; Barry Hart ; Daohong Zhou ; and Martin Hauer-Jensen , Division of
Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences,
1
2
Little Rock, AR ; Innovation Pathways, Palo Alto, CA ; and Central Arkansas Veterans Healthcare System,
3
Little Rock, AR
The severity of gastrointestinal (GI) and bone marrow (BM) injury is a critical determinant of
survival after exposure to a moderate or high dose total body radiation (TBI) in nuclear accidents or
radiological terrorism scenarios. A limited number of mitigating agents and treatments are currently
available against irradiation (IR)-induced tissue damage. It is well known that activation of transforming
growth factor beta (TGF-β) and subsequent induction of Smad2/3 phosphorylation play important roles
in IR-induced chronic fibrosis in many organs. In the present study, we utilized a newly developed small
molecule TGF-β type I receptor kinase inhibitor IPW-5371 to investigate whether TGF-β signaling pathway
plays a role in IR-induced acute GI and BM injury. Initially, we used EA.hy926 endothelial cell line and 32D
hematopoietic progenitor cell line as in vitro models. We exposed cells to 10.0 Gy irradiation and
measured phosphorylation status of Smad2/3 at different time points by phospho-flow cytometric
analysis. Exposure to IR significantly triggered Smad2/3 phosphorylation at 24h in both endothelial and
hematopoietic cells compared to un-irradiated controls. These effects were almost completely abolished
by 1 hour preincubation of the cells with 10 μM IPW-5371. Subsequently, we administered vehicle or IPW-
5371 (20 mg/kg, oral gavage) once to C57BL/6 mice at 4h before irradiation by gavage and then exposed
them to 8.5 Gy TBI. The effects of IPW-5371 on TBI-induced Smad2/3 phosphorylation in GI and BM were
examined 24h after TBI. As expected, TBI induced severe damage to intestine and BM and induced
Smad2/3 phosphorylation in intestinal epithelial cells and hematopoietic cells at 24 hours post exposure.
IPW-5371 administration significantly reduced phosphorylation of Smad2/3 induced by TBI. Assessment
of IR-induced injuries in GI and BM is ongoing. These results indicate that the small molecule inhibitor
IPW-5371 can efficiently inhibit the activation of TGF-β signaling pathway induced by IR in GI and BM.
IPW-5371 may have potential as a mitigator of IR-induced acute radiation syndrome and lethality.
(PS7-43) TP508 peptide prevents brain tumor relapse by sensitizing cancer stem cells to radiation
2
1
1
1
therapy. Stephanie Moya, BS ; Carla Kantara, PhD ; Meng Zhong, M.S. ; Laurie Sower, PhD ; and Darrell
1
1
Carney, PhD , The University of Texas Medical Branch, Galveston, TX and Chrysalis BioTherapeutics, Inc,
2
Galveston, TX
In 2014, approximately 70, 000 adults and 4, 500 children are expected to be diagnosed with brain
cancer in the U.S alone, making this disease the second leading cause of cancer related deaths in children
and young adults. Currently available therapies such as radio/chemotherapy are ineffective in completely
eradicating the tumor bulk, thus resulting in recurrence of the disease. This is partly due to the inability
375 | P a g e
the foci assay indicating that non-homologous end joining (NHEJ) pathway is involved for the
radioadaptive response in MCF-10A cells. These data suggest that nuclear DNA repair ability is conjugated
with enhanced mitochondrial bioenergetics regulated by mitochondria localized Cyclin B1/CDK1.
(PS7-42) Inhibition of TGF-β activation by small molecular IPW-5371 may protect against radiation-
1
1
1
1
induced intestinal and hematopoietic injury. Lijian Shao ; Rupak Pathak ; Wei Feng ; Jianhui Chang ;
1;3
1
1
1
2
Junru Wang ; Marjan Boerma ; Barry Hart ; Daohong Zhou ; and Martin Hauer-Jensen , Division of
Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences,
1
2
Little Rock, AR ; Innovation Pathways, Palo Alto, CA ; and Central Arkansas Veterans Healthcare System,
3
Little Rock, AR
The severity of gastrointestinal (GI) and bone marrow (BM) injury is a critical determinant of
survival after exposure to a moderate or high dose total body radiation (TBI) in nuclear accidents or
radiological terrorism scenarios. A limited number of mitigating agents and treatments are currently
available against irradiation (IR)-induced tissue damage. It is well known that activation of transforming
growth factor beta (TGF-β) and subsequent induction of Smad2/3 phosphorylation play important roles
in IR-induced chronic fibrosis in many organs. In the present study, we utilized a newly developed small
molecule TGF-β type I receptor kinase inhibitor IPW-5371 to investigate whether TGF-β signaling pathway
plays a role in IR-induced acute GI and BM injury. Initially, we used EA.hy926 endothelial cell line and 32D
hematopoietic progenitor cell line as in vitro models. We exposed cells to 10.0 Gy irradiation and
measured phosphorylation status of Smad2/3 at different time points by phospho-flow cytometric
analysis. Exposure to IR significantly triggered Smad2/3 phosphorylation at 24h in both endothelial and
hematopoietic cells compared to un-irradiated controls. These effects were almost completely abolished
by 1 hour preincubation of the cells with 10 μM IPW-5371. Subsequently, we administered vehicle or IPW-
5371 (20 mg/kg, oral gavage) once to C57BL/6 mice at 4h before irradiation by gavage and then exposed
them to 8.5 Gy TBI. The effects of IPW-5371 on TBI-induced Smad2/3 phosphorylation in GI and BM were
examined 24h after TBI. As expected, TBI induced severe damage to intestine and BM and induced
Smad2/3 phosphorylation in intestinal epithelial cells and hematopoietic cells at 24 hours post exposure.
IPW-5371 administration significantly reduced phosphorylation of Smad2/3 induced by TBI. Assessment
of IR-induced injuries in GI and BM is ongoing. These results indicate that the small molecule inhibitor
IPW-5371 can efficiently inhibit the activation of TGF-β signaling pathway induced by IR in GI and BM.
IPW-5371 may have potential as a mitigator of IR-induced acute radiation syndrome and lethality.
(PS7-43) TP508 peptide prevents brain tumor relapse by sensitizing cancer stem cells to radiation
2
1
1
1
therapy. Stephanie Moya, BS ; Carla Kantara, PhD ; Meng Zhong, M.S. ; Laurie Sower, PhD ; and Darrell
1
1
Carney, PhD , The University of Texas Medical Branch, Galveston, TX and Chrysalis BioTherapeutics, Inc,
2
Galveston, TX
In 2014, approximately 70, 000 adults and 4, 500 children are expected to be diagnosed with brain
cancer in the U.S alone, making this disease the second leading cause of cancer related deaths in children
and young adults. Currently available therapies such as radio/chemotherapy are ineffective in completely
eradicating the tumor bulk, thus resulting in recurrence of the disease. This is partly due to the inability
375 | P a g e
