Akt1/NFκB signaling pathway activation by a small molecule DMA confers radioprotection to intestinal epithelium in xenograft model
Authors: Vibha Tandon
Atul Ranjan
Vinod Tiwari
Manish Singh
Hemlata Nimesh
Mohammad Zahid Kamran
Journal: Free Radical Biology and Medicine (2017)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Acute radiation syndrome; Akt1/NFκB signaling; Radiation; Radioprotector; Tumor.
Affiliations: Chemical Biology Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India., Special Centre for Molecular Medicine, Jawaharlal Nehru University, Delhi 110067, India., Department of Cancer Biology, The University of Kansas Cancer Center, 3901 Rainbow Blvd, Kansas City, KS 66010, USA., Chemical Biology Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India; Special Centre for Molecular Medicine, Jawaharlal Nehru University, Delhi 110067, India. Electronic address: .

Abstract:  Normal tissue protection and recovery of radiation-induced damage are of paramount importance for development of radioprotector. Radioprotector which selectively protects normal tissues over cancerous tissues improves the therapeutic window of radiation therapy. In the present study, small bisbenzimidazole molecule, DMA (5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxy-phenyl)-5'-benzimidazolyl]-benzimidazole) was evaluated for in vivo radioprotective effects to selectively protect normal tissue over tumor with underlying molecular mechanism. Administration of single DMA dose prior to radiation has enhanced survival of Balb/c mice against sublethal and supralethal total body irradiation. DMA ameliorated radiation-induced damage of normal tissues such as hematopoietic (HP) and gastrointestinal tract (GI) system. Oxidative stress marker Malondialdehyde level was decreased by DMA whereas it maintained endogenous antioxidant status by increasing the level of reduced glutathione, glutathione reductase, glutathione-s-transferase, superoxide dismutase and total thiol content in hepatic tissue of irradiated mice. Mechanistic studies revealed that DMA treatment prior to radiation leads to Akt1/NFκB signaling which reduced radiation-induced genomic instability in normal cells. However, these pathways were not activated in tumor tissues when subjected to DMA treatment in similar conditions. Abrogation of Akt1 and NFκB genes resulted in no radioprotection by DMA and enhanced apoptosis against radiation. Plasma half-life of DMA was 3.5h and 2.65h at oral and intravenous dose respectively and 90% clearance was observed in 16h. In conclusion, these data suggests that DMA has potential to be developed as a safe radioprotective agent for radiation countermeasures and an adjuvant in cancer therapy. 

Retracted: No

PubPeer comments:
 Figure 5: Possible duplication between figure 5C and figure 5E![file] , 
 Figure 5E and Figure 6: Unusual similarity in bands showing different proteins.![file] , 
 Posting comparison of figure 6 vs full figure 5E![file] , 
 Figure 3C. Repeat pattern in images representing different treatment groups. ![file] , 
 #2 I had to rescale the bands, stretch them vertically, and increase their contrast to convince myself of the similarity. ![file] #4 Could the repeated black dots be an imaging artifact? , 
 #5 It s possible the black dots are an odd artifact. On the other hand, the similarity of the dots on the first band gave the gel images away. ,