Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study
Drug discovery field has tremendously progressed during last few decades, however, an effective radiation countermeasure agent for the safe administration to the victims of radiation exposure is still unavailable. This multi-model study is aimed at elucidating the mechanistic aspects of a novel podo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00750/full |
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| author | M. H. Yashavarddhan M. H. Yashavarddhan Sandeep K. Shukla Pankaj Chaudhary Nitya N. Srivastava Jayadev Joshi Mrutyunjay Suar Manju L. Gupta |
| author_facet | M. H. Yashavarddhan M. H. Yashavarddhan Sandeep K. Shukla Pankaj Chaudhary Nitya N. Srivastava Jayadev Joshi Mrutyunjay Suar Manju L. Gupta |
| author_sort | M. H. Yashavarddhan |
| collection | DOAJ |
| description | Drug discovery field has tremendously progressed during last few decades, however, an effective radiation countermeasure agent for the safe administration to the victims of radiation exposure is still unavailable. This multi-model study is aimed at elucidating the mechanistic aspects of a novel podophyllotoxin and rutin combination (henceforth referred as G-003M) in the hematopoietic radioprotection and its involvement in the DNA damage and repair signaling pathways. Using in silico study, we identified the binding sites and structural components of G-003M and validated in vitro. We further studied various in vivo endpoints related to the DNA repair and cell death pathways in mice pre-administered with G-003M, irradiated and subsequently euthanized to collect blood and bone marrow cells. In silico study showed the binding of podophyllotoxin to β-tubulin and presence of a functional hydroxyl group in the rutin, suggested their involvement in G2/M arrest and the free radical scavenging respectively. This experimentation was further validated through in vitro studies. In vivo mice studies confirmed that G-003M pre-administration attenuated DNA damage and enhanced repair after whole body exposure. We further noticed a decrease in the levels of γH2AX, p53BP1, and ATM kinase and an increase in the levels of DNA pk, Ku 80, Ligase IV, Mre 11, Rad 50 and NBS 1 in the blood and bone marrow cells of the G-003M pre-administered and irradiated mice. We noticed an overall increase in the pro-survival factors in the G-003M pre-treated and irradiated groups establishing the radioprotective efficacy of this formulation. The lead obtained from this study will certainly help in developing this formulation as a safe and effective radioprotector which could be used for humans against any planned or emergency exposure of radiation. |
| first_indexed | 2024-04-12T14:37:49Z |
| format | Article |
| id | doaj.art-1d4a628048894a75a271aff999f896f5 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T14:37:49Z |
| publishDate | 2017-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-1d4a628048894a75a271aff999f896f52022-12-22T03:29:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-10-01810.3389/fphar.2017.00750294066Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo StudyM. H. Yashavarddhan0M. H. Yashavarddhan1Sandeep K. Shukla2Pankaj Chaudhary3Nitya N. Srivastava4Jayadev Joshi5Mrutyunjay Suar6Manju L. Gupta7Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, IndiaKIIT School of Biotechnology, KIIT University, Bhubaneswar, IndiaDivision of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, IndiaCentre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, United KingdomDepartment of Pharmacology, University of Illinois at Chicago, Chicago, IL, United StatesDivision of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, IndiaKIIT School of Biotechnology, KIIT University, Bhubaneswar, IndiaDivision of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, IndiaDrug discovery field has tremendously progressed during last few decades, however, an effective radiation countermeasure agent for the safe administration to the victims of radiation exposure is still unavailable. This multi-model study is aimed at elucidating the mechanistic aspects of a novel podophyllotoxin and rutin combination (henceforth referred as G-003M) in the hematopoietic radioprotection and its involvement in the DNA damage and repair signaling pathways. Using in silico study, we identified the binding sites and structural components of G-003M and validated in vitro. We further studied various in vivo endpoints related to the DNA repair and cell death pathways in mice pre-administered with G-003M, irradiated and subsequently euthanized to collect blood and bone marrow cells. In silico study showed the binding of podophyllotoxin to β-tubulin and presence of a functional hydroxyl group in the rutin, suggested their involvement in G2/M arrest and the free radical scavenging respectively. This experimentation was further validated through in vitro studies. In vivo mice studies confirmed that G-003M pre-administration attenuated DNA damage and enhanced repair after whole body exposure. We further noticed a decrease in the levels of γH2AX, p53BP1, and ATM kinase and an increase in the levels of DNA pk, Ku 80, Ligase IV, Mre 11, Rad 50 and NBS 1 in the blood and bone marrow cells of the G-003M pre-administered and irradiated mice. We noticed an overall increase in the pro-survival factors in the G-003M pre-treated and irradiated groups establishing the radioprotective efficacy of this formulation. The lead obtained from this study will certainly help in developing this formulation as a safe and effective radioprotector which could be used for humans against any planned or emergency exposure of radiation.http://journal.frontiersin.org/article/10.3389/fphar.2017.00750/fullDNA damage and repaircell deathROScell cycleradioprotection |
| spellingShingle | M. H. Yashavarddhan M. H. Yashavarddhan Sandeep K. Shukla Pankaj Chaudhary Nitya N. Srivastava Jayadev Joshi Mrutyunjay Suar Manju L. Gupta Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study Frontiers in Pharmacology DNA damage and repair cell death ROS cell cycle radioprotection |
| title | Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study |
| title_full | Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study |
| title_fullStr | Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study |
| title_full_unstemmed | Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study |
| title_short | Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study |
| title_sort | targeting dna repair through podophyllotoxin and rutin formulation in hematopoietic radioprotection an in silico in vitro and in vivo study |
| topic | DNA damage and repair cell death ROS cell cycle radioprotection |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2017.00750/full |
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