More than 50% of all cancer patients will receive radiotherapy during the course of their cancer treatments; however, radiation-induced injury to normal tissues is the major cause of radiation treatment?related side effects and is a limiting factor in cancer radiotherapy. There is also growing public concern of nuclear terrorist attacks or industrial accidents. However, no safe, effective, FDA-approved radioprotectants are currently available. Two vitamin E homologues??-tocotrienol (?-T3) and ?-tocotrienol (?-T3)?are some of the most effective low-toxic radioprotective agents identified to date. Among all natural products tested to date, ?-T3 and ?-T3 were found to give the highest degree of protection to mice exposed to radiation doses that were otherwise lethal. Despite their potential as radioprotectants, ?- and ?-T3 have relatively short plasma elimination half-lives and, if not given by intravenous injection, low bioavailability, which limits their exposure time and concentration in systemic circulation and necessitates administration in large doses. The short plasma elimination half-lives are a result of their low affinity for ?-tocopherol transfer protein (?-TTP) and their high rates of metabolism. The low bioavailability of ?- and ?-T3 is caused, at least in part, by their high lipophilicity and low water solubility. Low ?-TTP affinity and low metabolic stability are also responsible for the low oral bioavailability of ?- and ?-T3 because oral dosing is subject to significant first-pass metabolism through the liver. Thus, to improve the potential therapeutic utility of ?- and ?-T3 as radioprotective agents, we propose to design and synthesize T3-based analogues with intrinsic radioprotective properties comparable to or better than those of ?- and ?-T3 but with reduced lipophilicity, increased ?-TTP affinity, and increased metabolic stability. For this purpose, we will pursue the following Specific Aims: 1) design and synthesize ?- and ?-T3 analogues; 2) determine ?-TTP binding and liver metabolism of ?- and ?-T3 analogues; 3) determine antioxidant and HMG-CoA reductase inhibitory properties of ?- and ?-T3 analogues; and 4) determine in vitro radioprotective properties of ?- and ?-T3 analogues. Our long-term goal is to develop these compounds into radioprotective drugs for human use. We expect that such compounds will also serve as research tools for studying biochemical mechanisms of radiation protection.

Public Health Relevance

No safe and effective radioprotectants are currently available to protect normal tissue from injury resulting from cancer radiotherapy or other types of exposure to ionizing-radiation exposure. The overall goal of this project is to carry out the studies necessary to develop vitamin E homologues into therapeutically useful radioprotective agents. These studies, if successful, will have an enormous impact on public health, given the number of cancer patients receiving radiotherapy and the growing concern of radiological and nuclear emergencies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM109005-01A1
Application #
8880640
Study Section
Special Emphasis Panel (ZGM1-TWD-A (1C))
Project Start
Project End
Budget Start
2015-06-24
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$268,200
Indirect Cost
$88,200
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Zhang, Xin; Zhang, Suping; Liu, Xingui et al. (2018) Oxidation resistance 1 is a novel senolytic target. Aging Cell :e12780
Alexander, Tyler C; Butcher, Hannah; Krager, Kimberly et al. (2018) Behavioral Effects of Focal Irradiation in a Juvenile Murine Model. Radiat Res 189:605-617
He, Liu-Jun; Yang, Dong-Lin; Li, Shi-Qiang et al. (2018) Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells. Bioorg Med Chem 26:3899-3908
Kiaei, Mahmoud; Balasubramaniam, Meenakshisundaram; Govind Kumar, Vivek et al. (2018) ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity for aggregation. Sci Rep 8:13102
Koturbash, Igor (2018) 2017 Michael Fry Award Lecture When DNA is Actually Not a Target: Radiation Epigenetics as a Tool to Understand and Control Cellular Response to Ionizing Radiation. Radiat Res 190:5-11
Luo, Yi; Shao, Lijian; Chang, Jianhui et al. (2018) M1 and M2 macrophages differentially regulate hematopoietic stem cell self-renewal and ex vivo expansion. Blood Adv 2:859-870
Alexander, Tyler C; Simecka, Christy M; Kiffer, Frederico et al. (2018) Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model. Behav Brain Res 346:21-28
Liu, Xingui; Wang, Yingying; Zhang, Xuan et al. (2018) Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation. Bioorg Med Chem 26:3925-3938
Nukala, Ujwani; Thakkar, Shraddha; Krager, Kimberly J et al. (2018) Antioxidant Tocols as Radiation Countermeasures (Challenges to be Addressed to Use Tocols as Radiation Countermeasures in Humans). Antioxidants (Basel) 7:
Yadlapalli, Jai Shankar K; Dogra, Navdeep; Walbaum, Anqi W et al. (2018) Pinprick hypo- and hyperalgesia in diabetic rats: Can diet content affect experimental outcome? Neurosci Lett 673:24-27

Showing the most recent 10 out of 81 publications