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Toxicol Lett. 2013 Oct 24;222(2):122-31. doi: 10.1016/j.toxlet.2013.06.210. Epub 2013 Jun 14.

Role of type-II pathway in apoptotic cell death induction by photosensitized CDRI-97/78 under ambient exposure of UV-B.

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1
Photobiology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, India.

Abstract

Novel trioxane 97/78, developed by Central Drug Research Institute (CDRI), Lucknow has shown promising antimalarial activity. Clinical experience of anti-malarial drugs registered the occurrence of phototoxicity in patients exposed with sunlight subsequent to medication. Photodegradation study has identified one photo-product up to 4h under UV-B/Sunlight by LC-MS/MS. UV-B irradiated 97/78 compound produced ¹O₂ via type-II dependent reaction mechanism, corroborated by its specific quencher. 2'-dGuO degradation and % tail development in photochemical as well as comet test, advocated the genotoxic potential of 97/78. The photocytotoxicity assays (MTT and NRU) on HaCaT cell line revealed the considerable decline in cell viability by 97/78. Cell cycle and Annexin V/PI double stain along with AO/EB demonstrated the G2/M phase arrest and apoptosis. Significant caspase-3 activity was measured in photoexcited 97/78 by colorimetric assay. Fluorescence stain with AO/JC-1 confirmed the lysosomal disruption and mitochondrial membrane destabilization by UV-B irradiated 97/78. Gene expression by RT-PCR showed significant upregulation of p21 and pro-apoptotic Bax, but no change observed in Bcl-2. In conclusion, the study highlights ROS mediated DNA damage, lysosomal and mitochondrial destabilization via upregulation of Bax and activation of caspase-3 which further leads to apoptosis.

KEYWORDS:

Antimalarial; DNA damage; LC–MS/MS; Mitochondrial membrane destabilization; UV-B

PMID:
23769964
DOI:
10.1016/j.toxlet.2013.06.210
[Indexed for MEDLINE]
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