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Ascorbyl stearate and ionizing radiation potentiate apoptosis through intracellular thiols and oxidative stress in murine T lymphoma cells.

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Relation http://ir.cftri.com/13409/
https://doi.org/10.1016/j.cbi.2017.12.028
 
Title Ascorbyl stearate and ionizing radiation potentiate apoptosis through
intracellular thiols and oxidative stress in murine T lymphoma cells.
 
Creator Shirish, D. Mane
Akhilender Naidu, K.
 
Subject 17 Vitamin Biochemistry
 
Description Ascorbyl stearate (Asc-s) is a derivative of ascorbic acid with better anti-tumour efficacy compared to its parent
compound ascorbic acid. In this study, we have examined radio-sensitizing effect of Asc-s in murine T cell
lymphoma (EL4) cells at 4 Gy. Asc-s and radiation treatment reduced cell proliferation, induced apoptosis in a
dose dependent manner by arresting the cells at S/G2-M phase of cell cycle. It also decreased the frequency of
cancer stem cells per se, with significantly higher decrease in combination with radiation treatment./Further,
Asc-s and radiation treatment increased the level of reactive oxygen species (ROS), drop in mitochondrial
membrane potential (MMP) and increased caspase-3 activity resulting in apoptosis of EL4 cells. Further it also
significantly decreased GSH/GSSG ratio due to binding of Asc-s with thiols. The increase in oxidative stress
induced by Asc-s and radiation treatment was abrogated by thiol antioxidants in EL4 cells. Interestingly, this
redox modulation triggered significant increase in protein glutathionylation in a time dependent manner. Asc-s
treatment resulted in glutathionylation of IKK, p50-NF-kB and mutated p53, thereby inhibiting cancer progression
during oxidative stress. Asc-s quenches GSH ensuing Asc-s + GSH adduct thereby further modulating
GSH/GSSG ratio as evident from HPLC and docking studies. The anti-tumour effect of Asc-s along with radiation
was studied by injecting EL4 cells in synegenicC57/BL6 male mice. Intraperitoneal injection of Asc-s followed by
radiation exposure at 4 Gy to the tumour bearing mice resulted in radio-sensitization which is evident from
significant regression of tumour as evident from tumour burden index. The survival study supports the data that
Asc-s pre-treatment enhances radio-sensitization in murine lymphoma. Our data, suggest that Asc-s and ionizing
radiation induced cell cycle arrest and apoptosis by perturbing redox balance through irreversible complexes of
thiols with Asc-s, disturbed mitochondrial membrane permeability and activation of caspase-3 in EL4 cells.
 
Date 2018
 
Type Article
PeerReviewed
 
Format pdf
 
Language en
 
Identifier http://ir.cftri.com/13409/1/Chemico-Biological%20Interactions%20281%20%282018%29%2037%E2%80%9350.pdf
Shirish, D. Mane and Akhilender Naidu, K. (2018) Ascorbyl stearate and ionizing radiation potentiate apoptosis through intracellular thiols and oxidative stress in murine T lymphoma cells. Chemico-Biological Interactions, 281. pp. 37-50. ISSN 0009-2797