The 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

Abstract

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.

Supplemental Ferulic Acid Inhibits Total Body Irradiation-Mediated Bone Marrow Damage, Bone Mass Loss, Stem Cell Senescence, and Hematopoietic Defect in Mice by Enhancing Antioxidant Defense Systems

“…Taken as a whole, it is suggested that NRF2 is a potential therapeutic target to ameliorate or prevent TBI-mediated oxidative injuries, as well as to regulate self-renewal, proliferation, and differentiation of stem cells [ 43 ]. Overall, our current findings with previous reports [ 9 , 24 ] strongly suggest that the ferulic-acid-induced radioprotection is closely associated with the enhanced or maintained antioxidant defense systems that are followed by NRF2 upregulation.…”

“…Although therapeutic radiation can cause severe damages to intact soft and hard tissues [ 20 , 21 ], TBI is required for cancer patients or in BM transplantation. Reduced bone mass accrual and BMD, increased ROS and oxidative stress, long-term residual BM injury, and stem cell senescence with the attendant hematopoietic defects are to be the hallmarks of TBI-mediated disorders [ 9 , 22 , 23 , 24 ]. Disruption of cellular redox balance and depletion of endogenous antioxidant defense systems are also the main events in TBI-mediated oxidative damages [ 9 , 25 ].…”

“…We previously found that, in addition to ferulic acid, dietary antioxidants, caffeic acid and coumaric acid prevent TBI-mediated damages of liver and spleen tissues and HSC senescence, as well as restore activities of endogenous antioxidant enzymes [ 9 ]. Caffeic acid also exhibited an autonomous ameliorating effect on HSC-senescence-associated long-term BM injury and mortality in TBI mice, and induced in vitro anticancer activity, thereby indicating its clinical usefulness as a supplemental drug for cancer patients [ 24 ]. Different to the previous studies [ 9 , 24 ], this study administered mice with ferulic acid via intraperitoneal injection once per day for 37 consecutive days (7 days before and 30 days after TBI), and TBI-associated phenotypes in mice were analyzed at various time points after TBI.…”

“…Caffeic acid also exhibited an autonomous ameliorating effect on HSC-senescence-associated long-term BM injury and mortality in TBI mice, and induced in vitro anticancer activity, thereby indicating its clinical usefulness as a supplemental drug for cancer patients [ 24 ]. Different to the previous studies [ 9 , 24 ], this study administered mice with ferulic acid via intraperitoneal injection once per day for 37 consecutive days (7 days before and 30 days after TBI), and TBI-associated phenotypes in mice were analyzed at various time points after TBI. These experimental approaches allow the impacts of radioprotective antioxidant on TBI-mediated systemic damages to be defined in regard to its long-term administration, as well as to evaluate a time-dependent alteration of TBI-associated characteristic phenotypes.…”

“…TBI-mediated defects in body growth and bone mass accrual can be associated with BM microenvironmental impairments that cause functional loss or dysregulated differentiation of BM-conserved stem cells. Indeed, exposure to TBI induced a long-term residual BM injury, depending on the exposed dose or time of TBI, and this negatively affected BM niches and bone homeostasis [ 16 , 24 ]. In addition to HSCs, TBI induced oxidative DNA damage of MSCs and defected their functionality [ 6 , 26 , 27 ].…”