Many patients receiving chemotherapy and/or ionizing radiation (IR) develop acute and residual (or long- term) bone marrow (BM) injury that limits the success of cancer treatment and adversely affects their quality of life. Acute myelosuppression is the result of the induction of apoptosis in the rapidly proliferating hematopoietic progenitor cells (HPCs) and to a lesser degree in the relatively quiescent hematopoietic stem cells (HSCs). Its clinical manifestations have been successfully managed by the use of various hematopoietic growth factors. In contrast, residual BM injury has been largely attributed to the induction of HSC senescence. However, neither the molecular mechanisms by which chemotherapy and/or IR induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate residual BM injury. Recent studies from our laboratory and others provide new insights into HSC damage. First, we have found that exposure of mice to a sublethal dose of total body irradiation (TBI) perturbs the balance of reduction/oxidation (redox) reactions ONLY in HSCs, leading to a persistent and prolonged increase in reactive oxygen species (ROS) production. Second, HSCs are more sensitive to ROS-induced oxidative damage than HPCs and other hematopoietic cells. Moreover, it appears that ROS injures HSCs not by a nonspecific cytotoxic effect as previously hypothesized. Instead, the damage is at least partially mediated by induction of cellular senescence through redox-dependent activation of the p38 mitogen-activated protein kinase (p38)-p16lnk4a (p16) pathway. Based on these novel findings, we hypothesize that chemotherapy and IR cause residual BM injury by SELECTIVELY inducing HSC senescence through ROS-mediated activation of the p38-p16 pathway. Thus, we predict that antioxidants can be used to effectively mitigate residual BM injury. Moreover, antioxidant therapy provides additional benefits to cancer patients by suppressing chemotherapy- and IR-induced genetic instability, a primary cause of secondary tumors and a contributing factor to the development of tumor resistance. Therefore, this strategy offers the promise of significantly improving the quality of life and increasing the efficacy of chemotherapy and radiotherapy for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA122023-04
Application #
7837743
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Prasanna, Pat G
Project Start
2007-07-01
Project End
2012-03-31
Budget Start
2010-05-07
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$275,500
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Demaria, Marco; O'Leary, Monique N; Chang, Jianhui et al. (2017) Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov 7:165-176
Kim, Ha-Neui; Chang, Jianhui; Shao, Lijian et al. (2017) DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age. Aging Cell 16:693-703
Wang, Yingying; Chang, Jianhui; Li, Xin et al. (2017) Low doses of oxygen ion irradiation cause long-term damage to bone marrow hematopoietic progenitor and stem cells in mice. PLoS One 12:e0189466
Wang, Yingying; Chang, Jianhui; Shao, Lijian et al. (2016) Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks. Radiat Res 185:630-7
Liu, Y Lucy; Yan, Yan; Webster, Cody et al. (2016) Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy. Blood 127:1912-22
Wang, Yingying; Boerma, Marjan; Zhou, Daohong (2016) Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases. Radiat Res 186:153-61
Wang, Yingying; Chang, Jianhui; Liu, Xingui et al. (2016) Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY) 8:2915-2926
Chang, Jianhui; Wang, Yingying; Shao, Lijian et al. (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22:78-83
Wu, Yuehan; Lee, Suk-Hee; Williamson, Elizabeth A et al. (2015) EEPD1 Rescues Stressed Replication Forks and Maintains Genome Stability by Promoting End Resection and Homologous Recombination Repair. PLoS Genet 11:e1005675
Xu, Guoshun; Wu, Hongying; Zhang, Junling et al. (2015) Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic Biol Med 87:15-25

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