title: Amelioration of radiation-induced hematopoietic syndrome by an antioxidant chlorophyllin through increased stem cell activity and modulation of hematopoiesis.
abstract: Hematopoietic stem cells and progenitor cells (HSPC) are low in abundance and exhibit high radiosensitivity and their ability to divide dramatically decreases following exposure to ionizing radiation. Our earlier studies have shown antiapoptotic, immune-stimulatory, and antioxidant effects of chlorophyllin, a constituent of the over the counter drug derifil. Here we describe the beneficial effects of chlorophyllin against radiation-induced hematopoietic syndrome. Chlorophyllin administration significantly enhanced the abundance of HSPC in vivo. It induced a transient cell cycle arrest in lineage-negative cells in the bone marrow. However, the chlorophyllin-treated mice exposed to whole body irradiation (WBI) had a significantly higher proportion of actively dividing HSPC in the bone marrow as compared to only WBI-exposed mice. It significantly increased the number of colony forming units (CFUs) by bone marrow cells in vitro and spleen CFUs in irradiated mice in vivo. Pharmacokinetic study showed that chlorophyllin had a serum half-life of 141.8 min in mice. Chlorophyllin upregulated antiapoptotic genes and antioxidant machinery via activation of prosurvival transcription factors Nrf-2 and NF-κB and increased the survival and recovery of bone marrow cells in mice exposed to WBI. Chlorophyllin stimulated granulocyte production in bone marrow and increased the abundance of peripheral blood neutrophils by enhancing serum levels of granulocyte-colony stimulation factor (GCSF). Most importantly, prophylactic treatment of mice with chlorophyllin significantly abrogated radiation-induced mortality. Chlorophyllin mitigates radiation-induced hematopoietic syndrome by increasing the abundance of hematopoietic stem cells, enhancing granulopoiesis, and stimulating prosurvival pathways in bone marrow cells and lymphocytes.
authors: Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors: Shweta
authors: S
authors: Suryavanshi
authors: Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors: Deepak
authors: D
authors: Sharma
authors: Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors: Rahul
authors: R
authors: Checker
authors: Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors: Maikho
authors: M
authors: Thoh
authors: Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
authors: Vikram
authors: V
authors: Gota
authors: Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India. Electronic address: sskumar@barc.gov.in.
authors: Santosh K
authors: SK
authors: Sandur
authors: Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors: Krishna B
authors: KB
authors: Sainis
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002735:Chlorophyllides / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011832:Radiation Injuries / Q000517:prevention & control*
chemical_list: D000975:Antioxidants; D002735:Chlorophyllides; C007020:chlorophyllin
keywords: Hematopoiesis; Hematopoietic stem and progenitor cells; NF-κB; Nrf-2; Radioprotection