Open AccessThe Long-lasting Radioprotective Effect of Caffeic Acid in Mice Exposed to Total Body Irradiation by Modulating Reactive Oxygen Species Generation and Hematopoietic Stem Cell Senescence-Accompanied Long-term Residual Bone Marrow Injury
Author(s) -
Hyun-Jaung Sim,
Govinda Bhattarai,
Joshua Lee,
Jeong-Chae Lee,
SungHo Kook
Publication year - 2019
Publication title -
aging and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.808
H-Index - 54
ISSN - 2152-5250
DOI - 10.14336/ad.2019.0208
Subject(s) - clonogenic assay , total body irradiation , senescence , reactive oxygen species , apoptosis , stem cell , bone marrow , progenitor cell , haematopoiesis , programmed cell death , dna damage , medicine , cancer research , oxidative stress , chemistry , immunology , pharmacology , biology , microbiology and biotechnology , biochemistry , chemotherapy , cyclophosphamide , dna
Total body irradiation (TBI) serves as an effectively curative therapy for cancer patients and adversely causes long-term residual bone marrow (BM) injury with premature senescence of hematopoietic stem cells (HSCs), which is mediated by increased production of reactive oxygen species (ROS). In the present study, we investigated how the exposure time of TBI in a mouse model affects HSCs and whether the treatment of caffeic acid (CA), a known dietary phenolic antioxidant, has a radioprotective effect. Single (S)-TBI at a sublethal dose (5 Gy) caused relatively higher induction of mitochondrial ROS and senescence-related factors in HSCs than those in hematopoietic progenitor cells (HPCs) and Lineage - Sca-1 + c-Kit + (LSK) cells, as well as reduced clonogenic formation and donor cell-derived reconstituting capacity. Repetitive double (D)-TBI (two months after the S-TBI at a dose of 5Gy) further weakened HSPC function via mitochondrial ROS accumulation and senescence-associated β-galactosidase (SA-β-gal) activity. Oral administration of CA (20 mg/kg) five times before and once immediately after TBI ameliorated ROS generation and TBI-induced HSC senescence and its radioprotective effect was long lasting in S-TBI mice but not in D-TBI mice. Further, supplementation of CA also induced apoptotic cell death of colon cancer cells. Collectively, these findings indicate that CA has a dual effect, ameliorating HSC senescence-accompanied long-term BM injury in S-TBI mice and stimulating apoptotic cell death of colon cancer cells.