Zileuton Alleviates Radiation-Induced Cutaneous Ulcers via Inhibition of Senescence-Associated Secretory Phenotype in Rodents.
Mineon ParkJiyoung NaSeo Young KwakSunhoo ParkHyewon KimSun-Joo LeeWon-Suk JangSeung-Bum LeeWon Il JangHyosun JangSehwan ShimPublished in: International journal of molecular sciences (2022)
Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.
Keyphrases
- radiation induced
- radiation therapy
- induced apoptosis
- dna damage
- endothelial cells
- wound healing
- cell cycle arrest
- single cell
- cell therapy
- stress induced
- healthcare
- endoplasmic reticulum stress
- cell death
- squamous cell carcinoma
- oxidative stress
- signaling pathway
- mass spectrometry
- bone marrow
- extracellular matrix
- cell proliferation
- soft tissue
- replacement therapy
- atomic force microscopy
- rectal cancer
- single molecule
- protein kinase