Bone marrow (BM) suppression is the primary cause of death after accidental or intentional exposure to a moderate or high dose of radiation and a common side effect of cancer therapy. The mechanisms whereby IR induces BM suppression have been largely attributed to the induction of apoptosis in hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We have provided the foremost direct evidence showing that HSCs and HPCs die by apoptosis, not necrosis, after exposure to a moderate dose of IR. Treatment of HSCs and HPCs in vitro with a broad-spectrum caspase inhibitor, MX1013 or z-VAD, inhibited IR-induced apoptosis (without conversion to necrotic cell death) and preserved their function. Furthermore, mice treated with MX1013 or z-VAD exhibited a significant reduction in IR-induced mortality, demonstrating that the preserved HSCs had the ability to reconstitute damaged BM in vivo. In contrast, various tumor cells die not by apoptosis but by reproductive cell death in response to IR and inhibition of caspase activity with a caspase inhibitor fails to protect these cells from IR-induced clonogenic cell death. Based on these novel findings, we hypothesize that activation of caspases mediates IR-induced BM suppression by the induction of HSC and HPC apoptosis. Furthermore, caspase inhibitors are novel radioprotectants that have the potential to be developed as new mechanism-based therapeutic agents to selectively protect BM but not tumor cells from IR-induced damage. To test our hypothesis, we will determine: (1) the sequence of IR- induced caspase activation and the role of individual caspases in IR-induced apoptosis in HSCs and HPCs in vitro;(2) the radioprotective effects of MX1013 (a lead drug candidate of antiapoptotic caspase inhibitors developed by Maxim) and/or G-CSF on total body irradiation (TBI)-induced BM suppression;and (3) the effects of MX1013 on IR-induced tumor cell killing and mutagenesis and genetic instability in normal cells in a mouse model. We expect that the proposed experiments will provide new insights into the role of caspases in IR-induced myelosuppression. This will allow us to develop novel and mechanism-based interventions to circumvent IR-induced BM toxicity, which are urgently needed as new medical countermeasures against nuclear terrorism. In addition, these new interventions could markedly improve the therapeutic efficacy of conventional cancer therapy by reducing normal tissue injury induced by radiation and chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086860-08
Application #
7776938
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
2000-09-01
Project End
2010-02-28
Budget Start
2010-02-01
Budget End
2010-02-28
Support Year
8
Fiscal Year
2010
Total Cost
$17,432
Indirect Cost
Name
Medical University of South Carolina
Department
Pathology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Diaz-Montero, C Marcela; Wang, Yong; Shao, Lijian et al. (2012) The glutathione disulfide mimetic NOV-002 inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress. Free Radic Biol Med 52:1560-8
Shao, Lijian; Feng, Wei; Lee, Kyung-Jong et al. (2012) A sensitive and quantitative polymerase chain reaction-based cell free in vitro non-homologous end joining assay for hematopoietic stem cells. PLoS One 7:e33499
Berbee, Maaike; Fu, Qiang; Boerma, Marjan et al. (2011) Reduction of radiation-induced vascular nitrosative stress by the vitamin E analog ?-tocotrienol: evidence of a role for tetrahydrobiopterin. Int J Radiat Oncol Biol Phys 79:884-91
Pazhanisamy, Senthil K; Li, Hongliang; Wang, Yong et al. (2011) NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability. Mutagenesis 26:431-5
Li, Hongliang; Wang, Yong; Pazhanisamy, Senthil K et al. (2011) Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin mitigates total body irradiation-induced long-term bone marrow suppression. Free Radic Biol Med 51:30-7
Wang, Yong; Liu, Lingbo; Zhou, Daohong (2011) Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury. Radiat Res 176:743-52
Wang, Yong; Kellner, Joshua; Liu, Lingbo et al. (2011) Inhibition of p38 mitogen-activated protein kinase promotes ex vivo hematopoietic stem cell expansion. Stem Cells Dev 20:1143-52
Shao, Lijian; Li, Hongliang; Pazhanisamy, Senthil K et al. (2011) Reactive oxygen species and hematopoietic stem cell senescence. Int J Hematol 94:24-32
Wu, Lixian; Shao, Lijian; An, Ningfei et al. (2011) IKK? regulates the repair of DNA double-strand breaks induced by ionizing radiation in MCF-7 breast cancer cells. PLoS One 6:e18447

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