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.
Highlights
Radioprotective effect of caffeic acid moderate or high-doses of Total body irradiation (TBI)-exposed cancer patients is clinically needed to remove the occurrence of secondary adverse events
The initial increase in reactive oxygen species (ROS) was reduced in S-TBI mice sacrificed at 2 months compared with 2 days after TBI, ROS levels in hematopoietic progenitor cells (HPCs), Lin-Sca-1+c-Kit+ cells (LSKs) and hematopoietic stem cells (HSCs) were still higher than in cells from control mice
D-TBI mice sacrificed 2 months after TBI showed a significantly higher ROS level in LSKs and HSCs than cells from control and even S-TBI mice (Fig. 1A). In both S-TBI and D-TBI mice, HSCs retained relatively higher ROS levels compared to HPCs and LSK cells. These results indicate that TBI increases immediately and persistently the production of mitochondrial ROS in bone marrow (BM)-conserved hematopoietic cells, of which HSCs are more vulnerable to TBI than HPCs and LSKs, and repetitive TBI leads to ROS accumulation
Summary
Radioprotective effect of caffeic acid moderate or high-doses of TBI-exposed cancer patients is clinically needed to remove the occurrence of secondary adverse events. The antioxidant effects of metformin and resveratrol in preventing BM injury are mostly proved in mice that have received single TBI and bred only for a short period after treatment [7, 8]. Such experimental models do not reflect the situation of cancer patients who must undergo subsequent cycles of radiotherapy as the occasion demands and require follow-up observations, as accumulated radiotoxic stress results in hematopoietic diseases such as hypoplastic anemia, leukemia and lymphoma. The application of radiotherapy with an anti-cancer drug as a curative agent for the treatment of metastatic colon cancer, the anti-cancer effect of CA in the colon cancer cell line CT26 was evaluated
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