Abstract
1,4-Naphthoquinone (NQ) is the parent molecule of many clinically approved anticancer, anti-infective, and antiparasitic drugs such as anthracycline, mitomycin, daunorubicin, doxorubicin, diospyrin, and malarone. Presence of NQ during a-irradiation (4Gy) significantly reduced the death of irradiated murine splenic lymphocytes in a dose dependent manner (0.05-liM), with complete protection at liM as assessed by PI staining. Radioprotection by NQ was further confirmed by inhibition of caspase activation, decrease in cell size, DNA-fragmentation, nuclear-blebbing and clonogenic assay. All trans retinoic acid which is inhibitor of Nrf-2 pathway, completely abrogated the radioprotective effect of NQ, suggesting that radioprotective activity of NQ may be due to activation of Nrf-2 signaling pathways. Further, addition of NQ to lymphocytes activated Nrf-2 in time dependent manner as shown by confocal microscopy, electrophoretic mobility shift assay and quantitative real time PCR. It also increased the expression of Nrf-2 dependent cytoprotective genes like hemeoxygenase-1, MnSOD, catalse as demonstrated by real time PCR and flowcytometry. NQ protected lymphocytes significantly against radiation-induced cell death even when added after irradiation. Complete protection was observed by addition of NQ up to 2 h after irradiation. However, percentage protection decreased with increasing time interval. These results suggested that NQ may offer protection to lymphocytes
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Khan, Nazir M;
Sandur, Santosh K;
Checker, Rahul;
Sharma, Deepak;
Poduval, T.B., E-mail: nazirbiotech@rediffmail.com
[1]
- Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai (India)
Citation Formats
Khan, Nazir M, Sandur, Santosh K, Checker, Rahul, Sharma, Deepak, and Poduval, T.B., E-mail: nazirbiotech@rediffmail.com.
1,4 Naphthoquinone protects radiation induced cell death and DNA damage in lymphocytes by activation Nrf2/are pathway and enhancing DNA repair.
India: N. p.,
2012.
Web.
Khan, Nazir M, Sandur, Santosh K, Checker, Rahul, Sharma, Deepak, & Poduval, T.B., E-mail: nazirbiotech@rediffmail.com.
1,4 Naphthoquinone protects radiation induced cell death and DNA damage in lymphocytes by activation Nrf2/are pathway and enhancing DNA repair.
India.
Khan, Nazir M, Sandur, Santosh K, Checker, Rahul, Sharma, Deepak, and Poduval, T.B., E-mail: nazirbiotech@rediffmail.com.
2012.
"1,4 Naphthoquinone protects radiation induced cell death and DNA damage in lymphocytes by activation Nrf2/are pathway and enhancing DNA repair."
India.
@misc{etde_22026945,
title = {1,4 Naphthoquinone protects radiation induced cell death and DNA damage in lymphocytes by activation Nrf2/are pathway and enhancing DNA repair}
author = {Khan, Nazir M, Sandur, Santosh K, Checker, Rahul, Sharma, Deepak, and Poduval, T.B., E-mail: nazirbiotech@rediffmail.com}
abstractNote = {1,4-Naphthoquinone (NQ) is the parent molecule of many clinically approved anticancer, anti-infective, and antiparasitic drugs such as anthracycline, mitomycin, daunorubicin, doxorubicin, diospyrin, and malarone. Presence of NQ during a-irradiation (4Gy) significantly reduced the death of irradiated murine splenic lymphocytes in a dose dependent manner (0.05-liM), with complete protection at liM as assessed by PI staining. Radioprotection by NQ was further confirmed by inhibition of caspase activation, decrease in cell size, DNA-fragmentation, nuclear-blebbing and clonogenic assay. All trans retinoic acid which is inhibitor of Nrf-2 pathway, completely abrogated the radioprotective effect of NQ, suggesting that radioprotective activity of NQ may be due to activation of Nrf-2 signaling pathways. Further, addition of NQ to lymphocytes activated Nrf-2 in time dependent manner as shown by confocal microscopy, electrophoretic mobility shift assay and quantitative real time PCR. It also increased the expression of Nrf-2 dependent cytoprotective genes like hemeoxygenase-1, MnSOD, catalse as demonstrated by real time PCR and flowcytometry. NQ protected lymphocytes significantly against radiation-induced cell death even when added after irradiation. Complete protection was observed by addition of NQ up to 2 h after irradiation. However, percentage protection decreased with increasing time interval. These results suggested that NQ may offer protection to lymphocytes activating repair pathways. Repair of radiation induced DNA strand breaks was studied by comet assay. Pretreatment of lymphocytes with NQ induced single strand breaks up to 6h but not double strand breaks in DNA. However, NQ mediated single strand breaks were repaired completely at longer time intervals. Addition of NQ to lymphocytes prior to 4 Gy a-radiation exposure showed decrease in the yield of DNA double strand breaks. The observed time-dependent decrease in the DNA strand breaks could be attributed to enhanced DNA repair in NQ treated lymphocytes. Furthermore, microarray analysis indicated that treatment of lymphocytes with NQ induces upregulation of several DNA repair genes including mismatch repair (Msh6, Pms2, and Rfc1), nucleotide and base excision repair pathways like pole4, parp1, parp4. Induction of these genes in NQ treated lymphocytes were confirmed by quantitative real time PCR. Further, treatment of lymphocytes with NQ resulted in increased expression of proteins as revealed by 2D protein blot analysis. Proteomic analysis of these spots corresponds to RIKEN protein which is known to exhibits as radio-resistance in the cells. Thus in addition to anti-cancer and anti-parasitic activity, NQ offered protection against a-radiation-induced cell death in lymphocytes via activation of Nrf-2/ARE and DNA repair pathways. (author)}
place = {India}
year = {2012}
month = {Jul}
}
title = {1,4 Naphthoquinone protects radiation induced cell death and DNA damage in lymphocytes by activation Nrf2/are pathway and enhancing DNA repair}
author = {Khan, Nazir M, Sandur, Santosh K, Checker, Rahul, Sharma, Deepak, and Poduval, T.B., E-mail: nazirbiotech@rediffmail.com}
abstractNote = {1,4-Naphthoquinone (NQ) is the parent molecule of many clinically approved anticancer, anti-infective, and antiparasitic drugs such as anthracycline, mitomycin, daunorubicin, doxorubicin, diospyrin, and malarone. Presence of NQ during a-irradiation (4Gy) significantly reduced the death of irradiated murine splenic lymphocytes in a dose dependent manner (0.05-liM), with complete protection at liM as assessed by PI staining. Radioprotection by NQ was further confirmed by inhibition of caspase activation, decrease in cell size, DNA-fragmentation, nuclear-blebbing and clonogenic assay. All trans retinoic acid which is inhibitor of Nrf-2 pathway, completely abrogated the radioprotective effect of NQ, suggesting that radioprotective activity of NQ may be due to activation of Nrf-2 signaling pathways. Further, addition of NQ to lymphocytes activated Nrf-2 in time dependent manner as shown by confocal microscopy, electrophoretic mobility shift assay and quantitative real time PCR. It also increased the expression of Nrf-2 dependent cytoprotective genes like hemeoxygenase-1, MnSOD, catalse as demonstrated by real time PCR and flowcytometry. NQ protected lymphocytes significantly against radiation-induced cell death even when added after irradiation. Complete protection was observed by addition of NQ up to 2 h after irradiation. However, percentage protection decreased with increasing time interval. These results suggested that NQ may offer protection to lymphocytes activating repair pathways. Repair of radiation induced DNA strand breaks was studied by comet assay. Pretreatment of lymphocytes with NQ induced single strand breaks up to 6h but not double strand breaks in DNA. However, NQ mediated single strand breaks were repaired completely at longer time intervals. Addition of NQ to lymphocytes prior to 4 Gy a-radiation exposure showed decrease in the yield of DNA double strand breaks. The observed time-dependent decrease in the DNA strand breaks could be attributed to enhanced DNA repair in NQ treated lymphocytes. Furthermore, microarray analysis indicated that treatment of lymphocytes with NQ induces upregulation of several DNA repair genes including mismatch repair (Msh6, Pms2, and Rfc1), nucleotide and base excision repair pathways like pole4, parp1, parp4. Induction of these genes in NQ treated lymphocytes were confirmed by quantitative real time PCR. Further, treatment of lymphocytes with NQ resulted in increased expression of proteins as revealed by 2D protein blot analysis. Proteomic analysis of these spots corresponds to RIKEN protein which is known to exhibits as radio-resistance in the cells. Thus in addition to anti-cancer and anti-parasitic activity, NQ offered protection against a-radiation-induced cell death in lymphocytes via activation of Nrf-2/ARE and DNA repair pathways. (author)}
place = {India}
year = {2012}
month = {Jul}
}